Eif4e inhibitors and uses thereof

ABSTRACT

The present invention provides compounds inhibiting elF4E activity, and compositions and methods of using thereof. Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with elF4E. Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer) such as those described herein.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibition of Eukaryotic initiation factor 4E (eIF4E). The inventionalso provides pharmaceutically acceptable compositions comprisingcompounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Eukaryotic initiation factor 4E (eIF4E) is a 24 kDa protein that plays akey role in the initiation of translation of mRNA. At the initiation ofmRNA translation, eIF4E binds to the 7-methylguanosine cap at the 5′ endof mRNAs, and forms a complex (called eIF4F) with the scaffoldingprotein eIF4G and the helicase eIF4A. The formation of this complex isrequired for the initiation of cap-dependent translation and thereforethe binding of eIF4E to eIF4G is a critical event in this process.

A number of studies have suggested that eIF4E is involved intumorigenesis and is a potential target in the field of oncology.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention, andpharmaceutically acceptable compositions thereof, are effective as eIF4Einhibitors. In one aspect, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with eIF4E. Such diseases,disorders, or conditions include cellular proliferative disorders (e.g.,cancer) such as those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and pharmaceutical compositionsthereof, are useful as inhibitors of eIF4E. Without wishing to be boundby any particular theory, it is believed that compounds of the presentinvention, and pharmaceutical compositions thereof, may inhibit theactivity of eIF4E and thus treat certain diseases, such as cancer.

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective as eIF4Einhibitors. In one aspect, the present invention provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is a bond, O, or S;-   R¹ is an optionally substituted ring selected from phenyl, an 8-10    membered bicyclic aromatic carbocyclic ring, a 5-6 membered    monocyclic heteroaromatic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or an 8-10 membered    bicyclic heteroaromatic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   L² is a C₁₋₈ bivalent straight or branched hydrocarbon chain,    wherein 1, 2, or 3 methylene units of the hydrocarbon chain are    optionally and independently replaced with —N(R)— or -Cy-;-   each R is independently selected from hydrogen or optionally    substituted —C₁₋₆ aliphatic;-   -Cy- is an optionally substituted bivalent ring selected from 3-6    membered monocyclic, saturated or partially unsaturated,    carbocyclylene, or 3-6 membered monocyclic, saturated or partially    unsaturated, heterocyclylene having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   R² is —COOR; and-   R³ is R, halogen, or an optionally substituted ring selected from    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6    membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or an 8-10    membered bicyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bicyclic ring” or “bicyclic ring system”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or having one or more units of unsaturation, having one ormore atoms in common between the two rings of the ring system. Thus, theterm includes any permissible ring fusion, such as ortho-fused orspirocyclic. As used herein, the term “heterobicyclic” is a subset of“bicyclic” that requires that one or more heteroatoms are present in oneor both rings of the bicycle. Such heteroatoms may be present at ringjunctions and are optionally substituted, and may be selected fromnitrogen (including N-oxides), oxygen, sulfur (including oxidized formssuch as sulfones and sulfonates), phosphorus (including oxidized formssuch as phosphates), boron, etc. In some embodiments, a bicyclic grouphas 7-12 ring members and 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or partially unsaturated, having at least one bridge. Asdefined by IUPAC, a “bridge” is an unbranched chain of atoms or an atomor a valence bond connecting two bridgeheads, where a “bridgehead” isany skeletal atom of the ring system which is bonded to three or moreskeletal atoms (excluding hydrogen). In some embodiments, a bridgedbicyclic group has 7-12 ring members and 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groupsare well known in the art and include those groups set forth below whereeach group is attached to the rest of the molecule at any substitutablecarbon or nitrogen atom. Unless otherwise specified, a bridged bicyclicgroup is optionally substituted with one or more substituents as setforth for aliphatic groups. Additionally or alternatively, anysubstitutable nitrogen of a bridged bicyclic group is optionallysubstituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 □ electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Each optional substituent on a substitutable carbon is a monovalentsubstituent independently selected from halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄ SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); (CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄ SR—, SC(S) SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S) SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —S(O)(NR^(∘))R^(∘); —S(O)₂N═C(NR^(∘) ₂)₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂;—OP(O)R^(∘))₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂.

Each R^(∘) is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted by a divalentsubstituent on a saturated carbon atom of R^(∘) selected from ═O and ═S;or each R^(∘) is optionally substituted with a monovalent substituentindependently selected from halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•).

Each R^(•) is independently selected from C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and wherein each R′ is unsubstituted or wherepreceded by halo is substituted only with one or more halogens; orwherein an optional substituent on a saturated carbon is a divalentsubstituent independently selected from ═O, ═S, ═NNR*₂, ═NNHC(O)R*,═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, or a divalent substituent bound to vicinalsubstitutable carbons of an “optionally substituted” group is—O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

When R* is C₁₋₆ aliphatic, R* is optionally substituted with halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isindependently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, andwherein each R^(•) is unsubstituted or where preceded by halo issubstituted only with one or more halogens.

An optional substituent on a substitutable nitrogen is independently—R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†),—C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂, —C(S)NR^(†) ₂,—C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein each R^(†) isindependently hydrogen, C₁₋₆ aliphatic, unsubstituted —OPh, or anunsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, two independent occurrences of R^(†), takentogether with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein when R^(†) is C₁₋₆ aliphatic, R^(†)is optionally substituted with halogen, —R^(•), -(haloR^(•)), —OH,—OR^(•), —O(haloR^(•)), —CN, —C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•),—NR^(•) ₂, or —NO₂, wherein each R^(•) is independently selected fromC₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, and wherein each R^(•) isunsubstituted or where preceded by halo is substituted only with one ormore halogens.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, of a provided compound comprises one ormore deuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits eIF4E with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 100 □M, less than about 50 □M, less than about 22.5 uM, lessthan about 15 uM, or less than about 7.5 uM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in eIF4E activity between a samplecomprising a compound of the present invention, or composition thereof,and eIF4E, and an equivalent sample comprising eIF4E, in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is a bond, O, or S;-   R¹ is an optionally substituted ring selected from phenyl, an 8-10    membered bicyclic aromatic carbocyclic ring, a 5-6 membered    monocyclic heteroaromatic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or an 8-10 membered    bicyclic heteroaromatic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   L² is a C₁₋₈ bivalent straight or branched hydrocarbon chain,    wherein 1, 2, or 3 methylene units of the hydrocarbon chain are    optionally and independently replaced with —N(R)— or -Cy-;-   each R is independently selected from hydrogen or optionally    substituted —C₁₋₆ aliphatic;-   -Cy- is an optionally substituted bivalent ring selected from 3-6    membered monocyclic, saturated or partially unsaturated,    carbocyclylene, or 3-6 membered monocyclic, saturated or partially    unsaturated, heterocyclylene having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   R² is —COOR; and-   R³ is R, halogen, or an optionally substituted ring selected from    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6    membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or an 8-10    membered bicyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur.

As defined generally above, L¹ is a bond, O, or S.

In some embodiments, L¹ is a bond. In some embodiments, L¹ is O. In someembodiments, L¹ is S.

In some embodiments, L¹ is selected from those depicted in Table 1,below.

As defined generally above, R¹ is an optionally substituted ringselected from phenyl, an 8-10 membered bicyclic aromatic carbocyclicring, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, oran 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R¹ is an optionally substituted phenyl.

In some embodiments, R¹ is an optionally substituted 8-10 memberedbicyclic aromatic carbocyclic ring.

In some embodiments, R¹ is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ isan optionally substituted 5-6 membered monocyclic heteroaromatic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R¹ is an optionally substituted 5-6membered monocyclic heteroaromatic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R¹ is an optionally substituted 5-6 membered monocyclicheteroaromatic ring having 1-2 heteroatoms independently selected fromnitrogen and oxygen.

In some embodiments, R¹ is an optionally substituted 8-10 memberedbicyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ isan optionally substituted 8-10 membered bicyclic heteroaromatic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R¹ is an optionally substituted 8-10membered bicyclic heteroaromatic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R¹ is an optionally substituted 8-10 membered bicyclicheteroaromatic ring having 1-2 nitrogen atoms.

In some embodiments, R¹ is unsubstituted phenyl.

In some embodiments, R¹ is phenyl substituted with 1-4 substituentsindependently selected from —CN, halogen, —OH, unsubstituted —C₁₋₆alkyl,unsubstituted —O—C₁₋₆alkyl, and an unsubstituted 3-8 membered monocyclicsaturated or partially unsaturated heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R¹ is phenyl substituted with 1-2 halogen. In someembodiments, R¹ is

In some embodiments, R¹ is an unsubstituted 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R¹ is anunsubstituted 5-6 membered monocyclic heteroaromatic ring having 1-2heteroatoms independently selected from nitrogen and oxygen.

In some embodiments, R¹ is a 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, substituted with 1-4 substituents independently selected from—CN, halogen, —OH, unsubstituted —C₁₋₆alkyl, unsubstituted —O—C₁₋₆alkyl,and an unsubstituted 3-8 membered monocyclic saturated or partiallyunsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is a5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatomsindependently selected from nitrogen and oxygen, substituted with 1-2halogen.

In some embodiments, R¹ is

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined generally above, L² is a C₁₋₈ bivalent straight or branchedhydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbonchain are optionally and independently replaced with —N(R)— or -Cy-.

In some embodiments, L² is a C₁₋₈ bivalent straight or branchedhydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbonchain are optionally and independently replaced with —N(R)—.

In some embodiments, L² is a C₁₋₈ bivalent straight or branchedhydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbonchain are optionally and independently replaced with -Cy-.

In some embodiments, L² is C₁₋₈ bivalent straight or branchedhydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain isoptionally replaced with —N(R)— or -Cy-.

In some embodiments, L² is

In some embodiments, L² is

In some embodiments, L² is

In some embodiments, L² is

In some embodiments, L² is selected from those depicted in Table 1,below.

As defined generally above, each R is independently selected fromhydrogen or optionally substituted —C₁₋₆ aliphatic.

In some embodiments, R is hydrogen.

In some embodiments, R is optionally substituted —C₁₋₆ aliphatic. Insome embodiments, R is optionally substituted —C₁₋₆ alkyl. In someembodiments, R is optionally substituted —C₁₋₃ alkyl.

In some embodiments, R is methyl. In some embodiments, R is ethyl. Insome embodiments, R is propyl or isopropyl.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined generally above, each -Cy- is independently an optionallysubstituted bivalent ring selected from a 3-6 membered monocyclic,saturated or partially unsaturated, carbocyclic ring, or a 3-6 memberedmonocyclic, saturated or partially unsaturated, heterocyclic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, -Cy- is an optionally substituted 3-6 memberedmonocyclic, saturated or partially unsaturated, bivalent carbocyclicring. In some embodiments, -Cy- is an optionally substituted 5 or 6membered monocyclic, saturated or partially unsaturated, bivalentcarbocyclic ring.

In some embodiments, -Cy- is an optionally substituted 3-6 memberedmonocyclic, saturated or partially unsaturated, bivalent heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, -Cy- is an optionallysubstituted 5 or 6 membered monocyclic, saturated or partiallyunsaturated, bivalent heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, -Cy- is an optionally substituted 5 or 6 memberedmonocyclic, saturated or partially unsaturated, bivalent heterocyclicring having 1-2 heteroatoms independently selected from nitrogen andoxygen.

In some embodiments, -Cy- is a 3-6 membered monocyclic saturatedbivalent carbocyclic ring optionally substituted 1-4 times withunsubstituted —C₁₋₆alkyl.

In some embodiments, -Cy- is a 3-6 membered monocyclic saturatedbivalent heterocyclic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, optionally substituted 1-4 times withunsubstituted —C₁₋₆alkyl. In some embodiments, -Cy- is a 3-6 memberedmonocyclic saturated bivalent heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen and oxygen, optionally substituted1-4 times with unsubstituted —C₁₋₆alkyl.

In some embodiments, -Cy- is selected from those depicted in Table 1,below.

As defined generally above, R² is —COOR.

In some embodiments, R² is —COOH. In some embodiments, R² is—COOC₁₋₆alkyl, wherein C₁₋₆alkyl is optionally substituted.

In some embodiments, R² is —COOCH₃ or —COOCH₂CH₃.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined generally above, R³ is R, halogen, or an optionallysubstituted ring selected from phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is R. In some embodiments, R³ is H.

In some embodiments, R³ is halogen. In some embodiments, R³ is Br.

In some embodiments, R³ is optionally substituted phenyl. In someembodiments, R³ is unsubstituted phenyl. In some embodiments, R³ isphenyl substituted with 1-4 substituents independently selected from—CN, halogen, —OH, unsubstituted —C₁₋₆alkyl, and unsubstituted—O—C₁₋₆alkyl.

In some embodiments, R³ is an optionally substituted 8-10 memberedbicyclic aromatic carbocyclic ring. In some embodiments, R³ is anunsubstituted 8-10 membered bicyclic aromatic carbocyclic ring. In someembodiments, R³ is an 8-10 membered bicyclic aromatic carbocyclic ringsubstituted with 1-4 substituents independently selected from —CN,halogen, —OH, unsubstituted —C₁₋₆alkyl, and unsubstituted —O—C₁₋₆alkyl.

In some embodiments, R³ is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R³ isan optionally substituted 5-6 membered monocyclic heteroaromatic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R³ is an unsubstituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R³ is a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, substitutedwith 1-4 substituents independently selected from —CN, halogen, —OH,unsubstituted —C₁₋₆alkyl, and unsubstituted —O—C₁₋₆alkyl.

In some embodiments, R³ is an optionally substituted 8-10 memberedbicyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R³ isan unsubstituted 8-10 membered bicyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R³ is an 8-10 membered bicyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, substituted with 1-4 substituents independently selected from—CN, halogen, —OH, unsubstituted —C₁₋₆alkyl, and unsubstituted—O—C₁₋₆alkyl.

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is selected from those depicted in Table 1,below.

Exemplary compounds of the invention are set forth in Table 1, below.

In some embodiments, the present invention provides a compound of Table1, or a pharmaceutically acceptable salt thereof.

TABLE 1 Exemplary Compounds

I-228

I-227

I-226

I-225

I-224

I-223

I-222

I-221

I-204

I-203

I-200

I-199

I-198

I-197

I-196

I-195

I-131

I-130

I-129

I-128

I-127

I-126

I-125

I-121

I-114

I-59

I-58

I-57

I-56

I-39

I-38

I-202

I-201

I-147

I-146

I-145

I-144

I-143

I-142

I-141

I-124

I-123

I-122

I-120

I-113

I-63

I-62

I-61

I-60

I-35

I-30

I-220

I-219

I-218

I-217

I-216

I-189

I-188

I-187

I-186

I-171

I-170

I-169

I-168

I-140

I-110

I-55

I-54

I-53

I-52

I-37

I-215

I-214

I-213

I-212

I-211

I-210

I-209

I-180

I-179

I-178

I-177

I-175

I-174

I-173

I-172

I-167

I-157

I-156

I-151

I-118

I-190

I-181

I-176

I-166

I-162

I-153

I-152

I-150

I-149

I-148

I-139

I-138

I-137

I-136

I-115

I-103

I-88

I-69

I-43

I-36

I-107

I-100

I-97

I-92

I-91

I-90

I-87

I-75

I-68

I-67

I-66

I-47

I-42

I-41

I-40

I-105

I-99

I-94

I-93

I-89

I-82

I-81

I-76

I-74

I-71

I-70

I-65

I-64

I-17

I-184

I-183

I-98

I-25

I-21

I-20

I-19

I-18

I-185

I-182

I-104

I-102

I-101

I-96

I-95

I-46

I-44

I-34

I-29

I-28

I-27

I-24

I-23

I-22

I-16

I-15

I-14

I-13

I-4

I-3

I-2

I-1

I-194

I-193

I-165

I-160

I-112

I-111

I-86

I-84

I-45

I-33

I-32

I-26

I-12

I-11

I-10

I-9

I-192

I-191

I-164

I-163

I-161

I-159

I-155

I-119

I-117

I-85

I-83

I-8

I-7

I-6

I-5

I-158

I-154

I-116

I-109

I-108

I-106

I-80

I-79

I-78

I-77

I-73

I-72

I-31

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

4. Formulation and Administration 4.1 Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention, or a pharmaceuticallyacceptable derivative thereof, and a pharmaceutically acceptablecarrier, adjuvant, or vehicle. The amount of compound in compositions ofthis invention is such that is effective to measurably inhibit eIF4E, ora mutant thereof, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit eIF4E, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, acomposition of this invention is formulated for administration to apatient in need of such composition. In some embodiments, a compositionof this invention is formulated for oral administration to a patient.

In some embodiments, the invention provides a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.

In some embodiments, the invention provides a pharmaceutical compositioncomprising a compound of Table 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.

In some embodiments, a compound of the invention, or a pharmaceuticallyacceptable derivative or composition thereof, is administered in asingle composition as a single dosage form.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof eIF4E, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

4.2. Co-Administration with One or More Other Therapeutic Agent

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents may be partof a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours apart.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with one or more other therapeuticagent simultaneously or sequentially in separate unit dosage forms ortogether in a single unit dosage form. Accordingly, the presentinvention provides a single unit dosage form comprising a compound ofthe current invention, one or more other therapeutic agent, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of a compound of the invention and one or more othertherapeutic agent (in those compositions which comprise an additionaltherapeutic agent as described above) that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.Preferably, a composition of the invention should be formulated so thata dosage of between 0.01-100 mg/kg body weight/day of a compound of theinvention can be administered.

In those compositions which comprise one or more other therapeuticagent, the one or more other therapeutic agent and a compound of theinvention may act synergistically. Therefore, the amount of the one ormore other therapeutic agent in such compositions may be less than thatrequired in a monotherapy utilizing only that therapeutic agent. In suchcompositions a dosage of between 0.01-1,000 μg/kg body weight/day of theone or more other therapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approved for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

4.2.1. Exemplary Other Therapeutic Agents

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

In some embodiments, one or more other therapeutic agent is aplatinum-based therapeutic, also referred to as platins. Platins causecross-linking of DNA, such that they inhibit DNA repair and/or DNAsynthesis, mostly in rapidly reproducing cells, such as cancer cells. Insome embodiments, a platinum-based therapeutic is selected fromcisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®,Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin®Sanofi-Aventis); nedaplatin (Aqupla®, Shionogi), picoplatin (PoniardPharmaceuticals); and satraplatin (JM-216, Agennix).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Envinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TKI258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is a proteasomeinhibitor. Approved proteasome inhibitors useful in the presentinvention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®,Amgen); and ixazomib (Ninlaro®, Takeda).

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGFβ trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFβ “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™ Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN₁₀₇); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410,adaphostin); 1) compounds targeting, decreasing or inhibiting theactivity of the epidermal growth factor family of receptor tyrosinekinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and theirmutants, such as compounds which target, decrease or inhibit theactivity of the epidermal growth factor receptor family are especiallycompounds, proteins or antibodies which inhibit members of the EGFreceptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 andErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva,OSI-774, C₁₋₁₀₃₃, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11,E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m)compounds targeting, decreasing or inhibiting the activity of the c-Metreceptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF, n) compounds targeting, decreasing orinhibiting the kinase activity of one or more JAK family members(JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited toPRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509,AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compoundstargeting, decreasing or inhibiting the kinase activity of PI3 kinase(PI3K) including but not limited to ATU-027, SF-1126, DS-7423,PBI-05204, GSK-2126458, Z STK-474, buparlisib, pictrelisib, PF-4691502,BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q)compounds targeting, decreasing or inhibiting the signaling effects ofhedgehog protein (Hh) or smoothened receptor (SMO) pathways, includingbut not limited to cyclopamine, vismodegib, itraconazole, erismodegib,and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, Z STK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; Zd6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

4.2.2. Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TGO2 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-de1ta24-hTNFa-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhlL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetlL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhlL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiments, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiments, the bystander cellscomprise tumor-associated antigen (TAA) negative cancer cells. In someembodiments, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GALS, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

5. Uses

Compounds and compositions described herein are generally useful for theinhibition of eIF4E or a mutant thereof.

The activity of a compound utilized in this invention as an inhibitor ofeIF4E, or a mutant thereof, may be assayed in vitro, in vivo or in acell line. In vitro assays include assays that determine inhibition ofeIF4E, or a mutant thereof. Alternate in vitro assays quantitate theability of the inhibitor to bind to eIF4E. Detailed conditions forassaying a compound utilized in this invention as an inhibitor of eIF4E,or a mutant thereof, are set forth in the Examples below.

Provided compounds are inhibitors of eIF4E and are therefore useful fortreating one or more disorders associated with activity of eIF4E. Thus,in certain embodiments, the present invention provides a method fortreating an eIF4E-mediated disorder comprising the step of administeringto a patient in need thereof a compound of the present invention, orpharmaceutically acceptable composition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

As used herein, the terms “eIF4E-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which eIF4E, or a mutant thereof, is known to play a role,including, but is not limited to, a cellular proliferative disorder. Insome embodiments, a cellular proliferative disorder is cancer asdescribed herein.

Cancer

Cancer includes, in some embodiments, without limitation, leukemias(e.g., acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemia, acute myeloblastic leukemia, acute promyelocytic leukemia,acute myelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,glioblastoma multiforme (GBM, also known as glioblastoma),medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,neurofibrosarcoma, meningioma, melanoma, neuroblastoma, andretinoblastoma).

In some embodiments, the cancer is glioma, astrocytoma, glioblastomamultiforme (GBM, also known as glioblastoma), medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma,melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g.Grade I—Pilocytic Astrocytoma, Grade II—d Low-grade Astrocytoma, GradeIII—Anaplastic Astrocytoma, or Grade IV—Glioblastoma (GBM)), chordoma,CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixedglioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma,metastatic brain tumor, oligodendroglioma, pituitary tumors, primitiveneuroectodermal (PNET) tumor, or schwannoma. In some embodiments, thecancer is a type found more commonly in children than adults, such asbrain stem glioma, craniopharyngioma, ependymoma, juvenile pilocyticastrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor,primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In someembodiments, the patient is an adult human. In some embodiments, thepatient is a child or pediatric patient.

Cancer includes, in another embodiment, without limitation,mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, gastrointestinal (gastric,colorectal, and duodenal), uterine cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, testicular cancer,chronic or acute leukemia, chronic myeloid leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma,fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one ormore of the foregoing cancers.

In some embodiments, the cancer is selected from hepatocellularcarcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tubecancer; papillary serous cystadenocarcinoma or uterine papillary serouscarcinoma (UPSC); prostate cancer; testicular cancer; gallbladdercancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma;rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma;anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer;pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, fallopian tube cancer, papillaryserous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC),hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma,rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer,adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma,pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associatedmalignant peripheral nerve sheath tumors (MPNST), Waldenstrom'smacroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is a solid tumor, such as a sarcoma,carcinoma, or lymphoma. Solid tumors generally comprise an abnormal massof tissue that typically does not include cysts or liquid areas. In someembodiments, the cancer is selected from renal cell carcinoma, or kidneycancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or livercancer; melanoma; breast cancer; colorectal carcinoma, or colorectalcancer; colon cancer; rectal cancer; anal cancer; lung cancer, such asnon-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC);ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, orfallopian tube cancer; papillary serous cystadenocarcinoma or uterinepapillary serous carcinoma (UPSC); prostate cancer; testicular cancer;gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bonesynovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewingsarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreaticcancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma,hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma,colorectal cancer, colon cancer, rectal cancer, anal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma,anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer,pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, braincancer, neurofibromatosis-1 associated malignant peripheral nerve sheathtumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroidcancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductalcarcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1associated malignant peripheral nerve sheath tumors (MPNST),Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is hepatocellular carcinoma (HCC). Insome embodiments, the cancer is hepatoblastoma. In some embodiments, thecancer is colon cancer. In some embodiments, the cancer is rectalcancer. In some embodiments, the cancer is ovarian cancer, or ovariancarcinoma. In some embodiments, the cancer is ovarian epithelial cancer.In some embodiments, the cancer is fallopian tube cancer. In someembodiments, the cancer is papillary serous cystadenocarcinoma. In someembodiments, the cancer is uterine papillary serous carcinoma (UPSC). Insome embodiments, the cancer is hepatocholangiocarcinoma. In someembodiments, the cancer is soft tissue and bone synovial sarcoma. Insome embodiments, the cancer is rhabdomyosarcoma. In some embodiments,the cancer is osteosarcoma. In some embodiments, the cancer isanaplastic thyroid cancer. In some embodiments, the cancer isadrenocortical carcinoma. In some embodiments, the cancer is pancreaticcancer, or pancreatic ductal carcinoma. In some embodiments, the canceris pancreatic adenocarcinoma. In some embodiments, the cancer is glioma.In some embodiments, the cancer is malignant peripheral nerve sheathtumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1associated MPNST. In some embodiments, the cancer is Waldenstrom'smacroglobulinemia. In some embodiments, the cancer is medulloblastoma.

In some embodiments, the cancer is Acute Lymphoblastic Leukemia (ALL),Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer,Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma,Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma,Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous SystemAtypical Teratoid/Rhabdoid Tumor, Central Nervous System EmbryonalTumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, CarcinoidTumor, Carcinoma of Unknown Primary, Central Nervous System Cancer,Cervical Cancer, Childhood Cancers, Chordoma, Chronic LymphocyticLeukemia (CLL), Chronic Myelogenous Leukemia (CML), ChronicMyeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ(DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoblastoma,Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma,Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, ExtrahepaticBile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, GallbladderCancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor,Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Ovarian GermCell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy CellLeukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer,Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, HypopharyngealCancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, KidneyCancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lipand Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS),Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, MaleBreast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, MerkelCell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancerwith Occult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome,Myelodysplastic/Myeloproliferative Neoplasm, Chronic MyelogenousLeukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma,Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, ParanasalSinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-HodgkinLymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer,Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer,Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal SinusCancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors ofIntermediate Differentiation, Pineoblastoma, Pituitary Tumor, PlasmaCell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary CentralNervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, RenalCell Cancer, Clear cell renal cell carcinoma, Renal Pelvis Cancer,Ureter Cancer, Transitional Cell Cancer, Retinoblastoma,Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sezary Syndrome, SkinCancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft TissueSarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with OccultPrimary, Squamous Cell Carcinoma of the Head and Neck (HNSCC), StomachCancer, Supratentorial Primitive Neuroectodermal Tumors, T-CellLymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thymic Carcinoma,Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter,Triple Negative Breast Cancer (TNBC), Gestational Trophoblastic Tumor,Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer, UterineCancer, Uterine Sarcoma, Waldenstrom Macroglobulinemia, or Wilms Tumor.

In certain embodiments, the cancer is selected from bladder cancer,breast cancer (including TNBC), cervical cancer, colorectal cancer,chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma(DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer,leukemia (acute and chronic), low-grade glioma, lung cancer (includingadenocarcinoma, non-small cell lung cancer, and squamous cellcarcinoma), Hodgkin's lymphoma, non-Hodgkin lymphoma (NHL), melanoma,multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostatecancer, renal cancer (including renal clear cell carcinoma and kidneypapillary cell carcinoma), and stomach cancer.

In some embodiments, the cancer is small cell lung cancer, non-smallcell lung cancer, colorectal cancer, multiple myeloma, acute myeloidleukemia (AML), acute lymphoblastic leukemia (ALL), pancreatic cancer,liver cancer, hepatocellular cancer, neuroblastoma, other solid tumorsor other hematological cancers.

In some embodiments, the cancer is small cell lung cancer, non-smallcell lung cancer, colorectal cancer, multiple myeloma, or AML.

The present invention further features methods and compositions for thediagnosis, prognosis and treatment of viral-associated cancers,including human immunodeficiency virus (HIV) associated solid tumors,human papilloma virus (HPV)-16 positive incurable solid tumors, andadult T-cell leukemia, which is caused by human T-cell leukemia virustype I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemiacharacterized by clonal integration of HTLV-I in leukemic cells (Seehttps://clinicaltrials.gov/ct2/show/study/NCT02631746); as well asvirus-associated tumors in gastric cancer, nasopharyngeal carcinoma,cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinomaof the head and neck, and Merkel cell carcinoma. (Seehttps://clinicaltrials.gov/ct2/show/study/NCT02488759; see alsohttps://clinicaltrials.gov/ct2/show/study/NCT0240886;https://clinicaltrials.gov/ct2/show/NCT02426892)

In some embodiments, the present invention provides a method fortreating a tumor in a patient in need thereof, comprising administeringto the patient compound II, or a pharmaceutical salt or compositionthereof, and an immuno-oncology agent as described herein. In someembodiments, the tumor comprises any of the cancers described herein. Insome embodiments, the tumor comprises melanoma cancer. In someembodiments, the tumor comprises breast cancer. In some embodiments, thetumor comprises lung cancer. In some embodiments the tumor comprisessmall cell lung cancer (SCLC). In some embodiments, the tumor comprisesnon-small cell lung cancer (NSCLC).

In some embodiments, the tumor is treated by arresting further growth ofthe tumor. In some embodiments, the tumor is treated by reducing thesize (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%,75%, 90% or 99% relative to the size of the tumor prior to treatment. Insome embodiments, tumors are treated by reducing the quantity of thetumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99%relative to the quantity of tumors prior to treatment.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the disease or condition, the particular agent, its mode ofadministration, and the like. The compounds and compositions, accordingto the method of the present invention, are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions will be decided by the attending physician within thescope of sound medical judgment. The specific effective dose level forany particular patient or organism will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “patient”, as used herein, means an animal, preferably a mammal,and most preferably a human.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the disease or disorder beingtreated. In certain embodiments, the compounds of the invention may beadministered orally or parenterally at dosage levels of about 0.01 mg/kgto about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound as described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The following examples are provided for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

All manipulations were carried out in a glass reaction tube equippedwith a magnetic stir bar under a nitrogen atmosphere. Unless otherwisementioned, solvents and reagents were purchased from commercial sourcesand used as received. The reaction was monitored by thin-layerchromatography carried out on silica gel plates and visualized under UVlight (254 nm). Analytical LC-MS was performed on an Agilent 1200infinity LC-MS system coupled with Agilent 6110 quadrupole massspectrometer and a XBRIGE Cis chromatography (4.6×50 mm, 3.5 um). Theanalysis was conducted at 2.0 mL/min flow rate using a linear gradientof 5 to 95% of B over 1.3 min, temperature: 50° C., (Buffer A: 0.01%TFA-containing H2O; Buffer B: 0.01% TFA-containing acetonitrile) or 1.8mL/min flow rate using a linear gradient of 10 to 95% of B over 1.5 min,temperature: 50° C. (Buffer A: 10 mmol NH₄HCO₃-containing H2O; Buffer B:acetonitrile). The NMR spectra were recorded in CDCl₃ or DMSO-d₆ on aBruker 400 MHz instrument with tetramethylsilane (TMS) as the internalstandard. NMR data are represented as follows: chemical shift (ppm),multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet),coupling constants in hertz (Hz), and integration.

ABBREVIATIONS DMA: Dimethyl Acetamide PE: Pentane EA: Ethyl AcetateEtOAc: Ethyl Acetate ESI-MS: Electrospray Ionization Mass Spectroscopy

TEA: Triethyl amine

DCM: Dichloromethane NBS: N-Bromo Succinimide

rt: Room temperatureRP-HPLC: Reverse phase high performance liquid chromatographyTFA: Trifluoroacetic acid

Example 1. Synthesis of Certain Exemplary Compounds 1.1

Synthesis of 1.1

A mixture of 4-bromo acetophenone (112 g, 565.6 mmol), oxazole (85.8 g,1244.4 mmol), tetrabutylammonium acetate (170.5 g, 565.6 mmol) andPalladium (II) acetate (Pd(OAc)₂; 6.3 g, 28.3 mmol) in DMA (1.2 L) wasstirred at 100° C. in a sealed-tube for 48 h. After cooling to rt, themixture was purified by flash silica gel chromatography (PE/EA=20:1 to5:1), concentrated and diluted with water (500 mL), extracted with EtOAc(3×500 mL), dried over Na₂SO₄, concentrated and washed with PE/EA (10:1)to give intermediate 1.1 (43.2 g, Y: 40%) as a yellow solid. ESI-MS(M+H)⁺: 188.1.

Synthesis of 1.2

To a mixture of intermediate 1.1 (43.2 g, 231.0 mmol) and TEA (70.0 g,693.0 mmol) in DCM (1.2 L) with stirring at 0° C. under N₂ was addeddropwise TMSOTf (102.6 g, 462.0 mmol). The mixture was allowed to warmto rt and stirred for 16 h, poured into water (500 mL), extracted withDCM (3×500 mL), dried over Na₂SO₄, and concentrated to afford a yellowoil. The oil was dissolved in THF (500 mL) followed by addition of NB S(49.3 g, 277.2 mmol) and reaction stirred at rt for 4 h. The mixture wasconcentrated and purified by flash silica gel chromatography (DCM 100%)to give intermediate 1.2 as a yellow solid (45.9 g, Y: 77%). ESI-MS(M+H)⁺: 266.0.

¹H NMR: (400 MHz, CDCl₃) δ: 8.06 (d, J=8.8 Hz, 2H), 7.99 (s, 1H), 7.78(d, J=8.8 Hz, 2H), 7.52 (s, 1H), 4.45 (s, 2H).

Synthesis of 1.3

A solution of intermediate 1.2 (45.9 g, 173.2 mmol) and sodiumthiocyanate (16.8 g, 207.8 mmol) in EtOH (340 mL) was stirred at rt for16 h. After cooling to rt, ice-water was added. The solid was collectedby filtration and dried to give intermediate 1.3 (36 g, Y: 85%) as ayellow solid. ESI-MS (M+H)⁺: 245.0.

¹H NMR: (400 MHz, CDCl₃) δ: 8.02-8.00 (m, 3H), 7.81 (d, J=8.4 Hz, 2H),7.55 (s, 1H), 4.74 (s, 2H).

Synthesis of 1.4

To a solution of intermediate 1.3 (2.1 g, 8.6 mmol) and2-pyrrolidineacetic acid, hydrochloride (2.1 g, 12.9 mmol) in t-BuOH (50mL) was added AcOH (5 mL). The mixture was stirred at 100° C. for 2 d.The mixture was concentrated and dried in vacuo to give intermediate 1.4(4.2 g) as crude yellow oil. The oil was used in the next step withoutany purification. ESI-MS (M+H)⁺: 356.1.

¹H NMR: (400 MHz, MeOD) δ: 8.27 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.75(d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.02 (s, 1H), 4.42-4.37 (m, 1H),3.60-3.55 (m, 1H), 3.46-3.40 (m, 1H), 3.22-3.18 (m, 1H), 2.48-2.42 (m,1H), 2.31-1.99 (m, 4H).

Synthesis of 1.5 & 1.6

To a solution of intermediate 1.4 (4.2 g, 8.6 mmol) in MeOH (100 mL) wasadded conc. H2SO₄ (1 mL) and stirred at reflux for 16 h. The mixture wasthen concentrated and purified by silica gel chromatography (PE/EA=5:1)to give intermediate 1.5 (600 mg). To a solution of intermediate 1.5(600 mg, 1.6 mmol) in THF (60 mL) was added NBS (202 mg, 1.1 mmol). Theresulting mixture was stirred at rt for 20 min. The mixture wasconcentrated and purified by silica gel chromatography (PE/EA=10:1) togive intermediate 1.6 (500 mg, Y: 13%, two steps) as a greenish solid.ESI-MS (M+H)⁺: 448.0.

¹H NMR: (400 MHz, CDCl₃) δ: 8.03 (d, J=8.4 Hz, 2H), 7.93 (s, 1H), 7.69(d, J=8.4 Hz, 2H), 7.38 (s, 1H), 4.40-4.36 (m, 1H), 3.68 (s, 3H),3.50-3.45 (m, 1H), 3.37-3.33 (m, 1H), 3.18-3.13 (m, 1H), 2.48-2.41 (m,1H), 2.26-2.20 (m, 1H), 2.09-2.02 (m, 2H), 1.96-1.91 (m, 1H).

Synthesis of I-36-I-39 General procedure for Suzuki coupling

To a solution of intermediate 1.6 (1.0 eq) and boronic acids (1.5 eq) indioxane/H₂O (10:1) was added Pd(dppf)Cl₂ (0.1 eq) and K₃PO₄ (3 eq). Themixture was stirred at 80° C. for 16 h under N₂ atmosphere. The solventwas removed and residue dissolved in MeOH (10 mL). LiOH (10 eq) wasadded and the mixture stirred at rt for 16 h. The mixture wasconcentrated and residue purified by preparative-RPHPLC (MeCN/H₂O with0.05% TFA as a mobile phase) to give the desired compounds I-36, I-37,I-38 and I-39.

I-36: yellow solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.3 (br s, 1H), 8.43 (s, 1H), 7.77 (d,J=8.4 Hz, 1H), 7.66-7.61 (m, 3H), 7.48 (d, J=8.8 Hz, 2H), 7.35-7.24 (m,5H), 3.92 (br s, 1H), 2.52-2.50 (m, 1H), 2.49-2.42 (m, 1H), 1.98-1.97(m, 1H), 0.94-0.91 (m, 6H).

I-37: yellow solid. ESI-MS (M+H)⁺: 436.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.29 (br s, 1H), 9.03 (s, 1H), 8.62 (s,2H), 8.46 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.70-7.67 (m, 3H), 7.49 (d,J=8.0 Hz, 2H), 3.98 (br s, 1H), 2.60-2.52 (m, 1H), 2.45-2.39 (m, 1H),1.98-1.97 (m, 1H), 0.94-0.91 (m, 6H).

I-38: yellow solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.41 (m, 3H), 7.95 (d, J=8.0 Hz, 1H),7.68-7.63 (m, 4H), 7.47 (d, J=8.4 Hz, 2H), 7.36-7.33 (m, 1H), 3.96 (brs, 1H), 2.43-2.32 (m, 2H), 1.99-1.97 (m, 1H), 0.94-0.91 (m, 6H).

I-39: yellow solid. ESI-MS (M+H)⁺: 473.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.17 (m, 1H), 11.21 (s, 1H), 8.39 (s,1H), 7.69-7.68 (m, 1H), 7.58 (s, 1H), 7.50-7.43 (m, 4H), 7.37 (d, J=8.0Hz, 1H), 7.29-7.27 (m, 1H), 7.07-7.04 (m, 1H), 6.93-6.91 (m, 1H), 6.13(s, 1H), 3.98 (br s, 1H), 2.50-2.42 (m, 2H), 2.02-1.97 (m, 1H),0.96-0.91 (m, 6H).

I-5: white solid. ESI-MS (M+H)⁺: 420.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.46 (br s, 1H), 8.44 (s, 1H), 7.66-7.61(m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.33-7.24 (m, 5H), 3.47 (d, J=4.4 Hz,2H), 1.17 (s, 6H).

I-6: yellow solid. ESI-MS (M+H)⁺: 422.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.43 (br s, 1H), 9.04 (s, 1H), 8.62 (s,2H), 8.46 (s, 1H), 8.01 (s, 1H), 7.71-7.67 (m, 3H), 7.49 (d, J=8.4 Hz,2H), 3.51 (d, J=5.2 Hz, 2H), 1.18 (s, 6H).

I-7: yellow solid. ESI-MS (M+H)⁺: 421.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.62 (br s, 1H), 8.45-8.41 (m, 3H), 7.86(s, 1H), 7.68-7.63 (m, 4H), 7.47 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H),3.48 (s, 2H), 1.18 (s, 6H).

I-8: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.41 (br s, 1H), 11.22 (s, 1H), 8.39 (s,1H), 7.62-7.58 (m, 2H), 7.50-7.43 (m, 4H), 7.38 (d, J=8.0 Hz, 1H), 7.28(t, J=2.4 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.13(s, 1H), 3.51 (d, J=5.6 Hz, 2H), 1.20 (s, 6H).

I-9: white solid. ESI-MS (M+H)⁺: 404.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.91 (br s, 1H), 8.44 (s, 1H), 7.68-7.63(m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.37-7.27 (m, 5H), 4.26 (t, J=8.4 Hz,2H), 4.12 (t, J=6.8 Hz, 2H), 3.65 (m, 1H).

I-10: white solid. ESI-MS (M+H)⁺: 406.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.95 (br s, 1H), 9.07 (s, 1H), 8.66 (s,2H), 8.47 (s, 1H), 7.72-7.69 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 4.30 (t,J=8.4 Hz, 2H), 4.17-4.14 (m, 2H), 3.67 (m, 1H).

I-11: yellow solid. ESI-MS (M+H)⁺: 405.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.16 (br s, 1H), 8.48-8.44 (m, 3H),7.70-7.66 (m, 4H), 7.47 (d, J=8.4 Hz, 2H), 7.39-7.36 (m, 1H), 4.27 (t,J=8.0 Hz, 2H), 4.14 (t, J=6.8 Hz, 2H), 3.64 (m, 1H).

I-12: yellow solid. ESI-MS (M+H)⁺: 443.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.27 (s, 1H), 8.40 (s, 1H), 7.59 (s, 1H),7.50 (d, J=8.0 Hz, 2H), 7.45-7.39 (m, 3H), 7.29 (t, J=2.8 Hz, 1H),7.07-7.05 (m, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.13 (s, 1H), 4.22-4.13 (m,4H), 3.33 (m, 1H).

I-13: light brown solid. ESI-MS (M+H)⁺: 418.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.98 (br s, 1H), 8.44 (s, 1H), 7.68-7.63(m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.35-7.26 (m, 5H), 4.27 (d, J=7.6 Hz,2H), 3.88 (d, J=8.0 Hz, 2H), 1.54 (s, 3H).

I-14: yellow solid. ESI-MS (M+H)⁺: 420.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 8.65-8.64 (m, 2H), 8.46 (s,1H), 7.71-7.68 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 4.30 (d, J=7.6 Hz, 2H),3.89 (d, J=7.6 Hz, 2H), 1.53 (s, 3H).

I-15: yellow solid. ESI-MS (M+H)⁺: 419.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.40-8.35 (m, 3H), 7.62-7.58 (m, 4H), 7.39(d, J=8.4 Hz, 2H), 7.31-7.28 (m, 1H), 4.21 (d, J=7.6 Hz, 2H), 3.82 (d,J=8.0 Hz, 2H), 1.46 (s, 3H).

I-16: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.25 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H),7.50 (d, J=8.4 Hz, 2H), 7.45-7.39 (m, 3H), 7.29 (t, J=2.4 Hz, 1H),7.09-7.05 (m, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.13 (s, 1H), 4.29 (d, J=7.6Hz, 2H), 3.87 (d, J=7.6 Hz, 2H), 1.54 (s, 3H).

I-17: white solid. ESI-MS (M+H)⁺: 358.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.45 (s, 1H), 8.23 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.80 (m, 1H), 7.74-7.70 (m, 3H), 7.17 (s, 1H), 3.46-3.38 (m,2H), 2.74-2.71 (m, 1H), 1.54-1.50 (m, 2H), 1.37-1.33 (m, 2H), 0.90 (t,J=7.2 Hz, 3H).

I-18: white solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.36 (br s, 1H), 8.43 (s, 1H), 7.88 (brs, 1H), 7.66 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H),7.35-7.25 (m, 5H), 3.47-3.39 (m, 2H), 2.74-2.71 (m, 1H), 1.54-1.49 (m,2H), 1.38-1.33 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

I-19: yellow solid. ESI-MS (M+H)⁺: 436.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.63 (s, 2H), 8.46 (s, 1H),8.17 (br s, 1H), 7.71-7.68 (m, 3H), 7.50 (d, J=8.8 Hz, 2H), 3.49-3.43(m, 2H), 2.74-2.71 (m, 1H), 1.54-1.50 (m, 2H), 1.38-1.32 (m, 2H), 0.90(t, J=7.2 Hz, 3H).

I-20: yellow solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.45-8.41 (m, 3H), 8.01-8.00 (m, 1H),7.68-7.64 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.37-7.34 (m, 1H), 3.47-3.40(m, 2H), 2.70-2.69 (m, 1H), 1.53-1.48 (m, 2H), 1.38-1.31 (m, 2H), 0.90(t, J=6.8 Hz, 3H).

I-21: yellow solid. ESI-MS (M+H)⁺: 473.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.39 (s, 1H), 7.76 (br s, 1H), 7.59 (s,1H), 7.51-7.45 (m, 4H), 7.39 (d, J=8.0 Hz, 1H), 7.29 (t, J=2.8 Hz, 1H),7.07 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.13 (s, 1H), 3.49-3.40(m, 2H), 2.73-2.70 (m, 1H), 1.54-1.53 (m, 2H), 1.39-1.35 (m, 2H), 0.92(t, J=7.2 Hz, 3H).

I-22: yellow solid. ESI-MS (M+H)⁺: 406.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.36 (br s, 1H), 8.43 (s, 1H), 7.76-7.61(m, 4H), 7.49 (d, J=8.4 Hz, 2H), 7.35-7.24 (m, 5H), 4.10-4.09 (m, 1H),2.64-2.59 (m, 1H), 2.46-2.44 (m, 1H), 1.24 (t, J=6.0 Hz, 3H).

I-23: yellow solid. ESI-MS (M+H)⁺: 408.0.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.39 (br s, 1H), 9.04 (s, 1H), 8.63 (s,2H), 8.46 (s, 1H), 8.10-8.08 (m, 1H), 7.70-7.68 (m, 3H), 7.50 (d, J=8.8Hz, 2H), 4.10-4.09 (m, 1H), 2.64-2.59 (m, 1H), 2.49-2.43 (m, 1H), 1.25(d, J=6.4 Hz, 3H).

I-24: yellow solid. ESI-MS (M+H)⁺: 407.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.54 (br s, 1H), 8.45-8.41 (m, 3H),7.95-7.93 (m, 1H), 7.68-7.63 (m, 4H), 7.47 (d, J=8.4 Hz, 2H), 7.37-7.34(m, 1H), 4.10-4.07 (m, 1H), 2.64-2.59 (m, 1H), 2.42-2.36 (m, 1H), 1.25(d, J=6.4 Hz, 3H).

I-25: yellow solid. ESI-MS (M+H)⁺: 445.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.22 (s, 1H), 8.39 (s, 1H), 7.67 (d,J=8.0 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 4H), 7.38 (d, J=8.4 Hz, 1H),7.28 (t, J=2.4 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.93 (m, 1H), 6.13 (s,1H), 4.16-4.10 (m, 1H), 2.72-2.66 (m, 1H), 2.45-2.39 (m, 1H), 1.27 (d,J=6.4 Hz, 3H).

I-26: yellow solid. ESI-MS (M+H)⁺: 330.1.

¹H NMR: (400 MHz, MeOD) δ: 8.27 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.75(d, J=8.4 Hz, 2H), 7.54 (s, 1H), 6.94 (s, 1H), 3.67-3.62 (m, 2H),3.49-3.44 (m, 2H), 2.94-2.89 (m, 1H), 1.26 (d, J=7.2 Hz, 3H).

I-27: yellow solid. ESI-MS (M+H)⁺: 406.0.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.31 (br s, 1H), 8.43 (s, 1H), 7.88 (t,J=5.6 Hz, 1H), 7.66 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz,2H), 7.33-7.24 (m, 5H), 3.56-3.50 (m, 1H), 3.35-3.28 (m, 1H), 2.83-2.74(m, 1H), 1.14 (d, J=7.2 Hz, 3H).

I-28: yellow solid. ESI-MS (M+H)⁺: 408.0.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.63 (s, 2H), 8.46 (s, 1H),8.19-8.13 (m, 1H), 7.71-7.68 (m, 3H), 7.50 (d, J=8.4 Hz, 2H), 3.57-3.51(m, 1H), 3.39-3.35 (m, 1H), 2.78-2.73 (m, 1H), 1.13 (d, J=6.4 Hz, 3H).

I-29: yellow solid. ESI-MS (M+H)⁺: 407.0.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.34 (br s, 1H), 8.45-8.41 (m, 3H),8.04-8.01 (m, 1H), 7.68-7.63 (m, 4H), 7.49-7.46 (m, 2H), 7.37-7.34 (m,1H), 3.58-3.51 (m, 1H), 3.37-3.35 (m, 1H), 2.83-2.74 (m, 1H), 1.14 (d,J=7.2 Hz, 3H).

I-30: yellow solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.22 (s, 1H), 8.39 (s, 1H), 7.76 (br s,1H), 7.58 (s, 1H), 7.50-7.44 (m, 4H), 7.38 (d, J=7.6 Hz, 1H), 7.29-7.28(m, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.92 (d, J=6.8 Hz, 1H), 6.13 (s, 1H),3.55-3.53 (m, 1H), 3.40-3.35 (m, 1H), 2.80-2.75 (m, 1H), 1.16 (d, J=7.2Hz, 3H).

I-35: yellow solid. ESI-MS (M+H)⁺: 356.1.

¹H NMR: (400 MHz, MeOD) δ: 8.27 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.75(d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.02 (s, 1H), 4.42-4.37 (m, 1H),3.60-3.55 (m, 1H), 3.46-3.40 (m, 1H), 3.22-3.18 (m, 1H), 2.48-2.42 (m,1H), 2.31-1.99 (m, 4H).

I-36: yellow solid. ESI-MS (M+H)⁺: 432.1.

¹H NMR: (400 MHz, MeOD) δ: 8.25 (s, 1H), 7.66-7.55 (m, 4H), 7.52 (s,1H), 7.32-7.25 (m, 5H), 4.37 (br s, 1H), 3.61-3.55 (m, 1H), 3.49-3.39(m, 1H), 3.15-3.09 (m, 1H), 2.50-2.44 (m, 1H), 2.28-2.01 (m, 4H).

I-37: yellow solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, MeOD) δ: 8.97 (s, 1H), 8.63 (s, 2H), 8.28 (s, 1H),7.74 (d, J=8.0 Hz, 2H), 7.59-7.57 (m, 3H), 4.43-4.41 (m, 1H), 3.64-3.59(m, 1H), 3.51-3.47 (m, 1H), 3.14-3.10 (m, 1H), 2.53-2.47 (m, 1H),2.32-2.04 (m, 4H).

I-38: yellow solid. ESI-MS (M+H)⁺: 432.8.

¹H NMR: (400 MHz, MeOD) δ: 8.40 (s, 2H), 8.27 (s, 1H), 7.75-7.69 (m,3H), 7.57-7.55 (m, 3H), 7.40-7.36 (m, 1H), 4.39 (br s, 1H), 3.62-3.58(m, 1H), 3.50-3.46 (m, 1H), 3.15-3.11 (m, 1H), 2.52-2.46 (m, 1H),2.31-2.03 (m, 4H).

I-39: yellow solid. ESI-MS (M+H)⁺: 470.8.

¹H NMR: (400 MHz, MeOD) δ: 8.20 (s, 1H), 7.54-7.48 (m, 4H), 7.42 (s,1H), 7.39 (d, J=8.0 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 7.08 (t, J=7.6 Hz,1H), 6.96 (d, J=7.2 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.42 (br s, 1H),3.62-3.58 (m, 1H), 3.51-3.45 (m, 1H), 3.23-3.19 (m, 1H), 2.53-2.47 (m,1H), 2.32-2.01 (m, 4H).

I-31: yellow solid. ESI-MS (M+H)⁺:432.2.

¹H NMR: (400 MHz, MeOD) δ: 8.25 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55(d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.33-7.26 (m, 5H), 4.17-4.13 (m, 1H),3.87-3.82 (m, 1H), 3.37-3.34 (m, 1H), 3.27-3.22 (m, 1H), 2.73-2.66 (m,1H), 2.18-2.12 (m, 1H), 1.89-1.70 (m, 3H).

I-32: yellow solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.62 (br s, 1H), 9.06 (s, 1H), 8.66 (s,2H), 8.47 (s, 1H), 7.72-7.69 (m, 3H), 7.51 (d, J=8.4 Hz, 2H), 4.03-3.99(m, 1H), 3.74-3.71 (m, 1H), 3.34-3.22 (m, 2H), 2.62-2.56 (m, 1H),2.02-1.98 (m, 1H), 1.78-1.57 (m, 3H).

I-33: yellow solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.47-8.38 (m, 4H), 7.69-7.65 (m, 4H), 7.48(d, J=8.4 Hz, 2H), 7.38-7.35 (m, 1H), 4.02-3.97 (m, 1H), 3.79-3.73 (m,1H), 3.26-3.15 (m, 2H), 2.47-2.41 (m, 1H), 2.03-1.97 (m, 1H), 1.77-1.73(m, 1H), 1.63-1.55 (m, 2H).

I-34: yellow solid. ESI-MS (M+H)⁺: 471.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 8.39 (s, 1H), 7.58 (s, 1H),7.51-7.45 (m, 4H), 7.40 (d, J=8.0 Hz, 1H), 7.29-7.28 (m, 1H), 7.08 (t,J=7.6 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.13-6.12 (m, 1H), 4.05-4.01 (m,1H), 3.77-3.72 (m, 1H), 3.29-3.19 (m, 2H), 2.58-2.54 (m, 1H), 2.04-1.97(m, 1H), 1.79-1.74 (m, 1H), 1.69-1.59 (m, 2H).

I-40: yellow solid. ESI-MS (M+H)⁺: 418.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 7.67-7.63 (m, 3H), 7.50 (d,J=8.4 Hz, 2H), 7.35-7.25 (m, 5H), 3.63 (d, J=6.8 Hz, 2H), 3.47 (t, J=6.8Hz, 2H), 3.25-3.21 (m, 1H), 2.26-2.21 (m, 2H).

I-41: yellow solid. ESI-MS (M+H)⁺: 420.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.63 (s, 2H), 8.47 (s, 1H),7.72-7.69 (m, 3H), 7.51 (d, J=8.4 Hz, 2H), 3.66 (d, J=6.4 Hz, 2H), 3.50(t, J=6.8 Hz, 2H), 3.27-3.23 (m, 1H), 2.28-2.23 (m, 2H).

I-42: yellow solid. ESI-MS (M+H)⁺: 419.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.45-8.41 (m, 3H), 7.69-7.64 (m, 4H), 7.49(d, J=8.4 Hz, 2H), 7.37-7.34 (m, 1H), 3.65-3.62 (m, 2H), 3.49-3.47 (m,2H), 3.18-3.17 (m, 1H), 2.24-2.20 (m, 2H).

I-43: yellow solid. ESI-MS (M+H)⁺: 457.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H),7.51-7.46 (m, 4H), 7.39 (d, J=8.0 Hz, 1H), 7.29 (t, J=2.4 Hz, 1H), 7.07(t, J=7.2 Hz, 1H), 6.94-6.92 (m, 1H), 6.13 (d, J=2.0 Hz, 1H), 3.66 (d,J=6.8 Hz, 2H), 3.51-3.48 (m, 2H), 3.25-3.22 (m, 1H), 2.26-2.23 (m, 2H).

I-44: yellow solid. ESI-MS (M+H)⁺: 418.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.43 (s, 1H), 7.82-7.80 (br s, 1H), 7.66(s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.32-7.23 (m,5H), 3.52 (br s, 2H), 1.09-0.99 (m, 4H).

I-45: yellow solid. ESI-MS (M+H)⁺: 420.2.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.03 (s, 1H), 8.62 (s, 2H), 8.46 (s, 1H),8.13 (br s, 1H), 7.71-7.67 (m, 3H), 7.48 (d, J=8.4 Hz, 2H), 3.70 (s,2H), 1.08-0.97 (m, 4H).

I-46: yellow solid. ESI-MS (M+H)⁺: 419.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.40 (m, 3H), 8.01-7.98 (m, 1H),7.68-7.62 (m, 4H), 7.46 (d, J=8.4 Hz, 2H), 7.36-7.33 (m, 1H), 3.54 (s,2H), 1.08-0.99 (m, 4H).

I-47: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.22 (s, 1H), 8.39 (s, 1H), 7.73 (br s,1H), 7.58 (s, 1H), 7.50-7.42 (m, 4H), 7.38 (d, J=8.4 Hz, 1H), 7.28 (t,J=2.8 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.92 (d, J=6.8 Hz, 1H), 6.12 (s,1H), 3.56 (s, 2H), 1.10-1.02 (m, 4H).

I-52: white solid. ESI-MS (M+H)⁺: 432.1.

¹H NMR: (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.59-7.52 (m, 4H), 7.32-7.26(m, 6H), 4.05-4.02 (m, 2H), 3.18 (t, J=11.0 Hz, 2H), 2.63-2.60 (m, 1H),2.10-2.08 (m, 2H), 1.95-1.86 (m, 2H).

I-53: yellow solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, CDCl₃) δ: 9.04 (s, 1H), 8.61 (s, 2H), 7.92 (s, 1H),7.62-7.52 (m, 4H), 7.36 (s, 1H), 4.07-4.03 (m, 2H), 3.25 (t, J=10.8 Hz,2H), 2.66-2.65 (m, 1H), 2.12-2.10 (m, 2H), 1.95-1.88 (m, 2H).

I-54: yellow solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.56-8.47 (m, 2H), 7.91 (s, 1H), 7.58-7.53(m, 5H), 7.34 (s, 1H), 7.22-7.19 (m, 1H), 4.06-4.01 (m, 2H), 3.24-3.18(m, 2H), 2.64-2.63 (m, 1H), 2.11-2.08 (m, 2H), 1.95-1.87 (m, 2H).

I-55: yellow solid. ESI-MS (M+H)⁺: 471.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.21 (s, 1H), 7.85 (s, 1H), 7.56 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.16-7.13 (m,2H), 7.08 (d, J=7.2 Hz, 1H), 6.39 (s, 1H), 4.10-4.06 (m, 2H), 3.24-3.18(m, 2H), 2.64-2.63 (m, 1H), 2.13-2.09 (m, 2H), 1.98-1.92 (m, 2H).

I-56: yellow solid. ESI-MS (M+H)⁺: 433.8.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 7.67-7.63 (m, 3H), 7.50 (d,J=8.4 Hz, 2H), 7.38-7.28 (m, 5H), 4.32-4.29 (m, 1H), 4.02-3.89 (m, 2H),3.73-3.71 (m, 1H), 3.58-3.55 (m, 1H), 3.41-3.35 (m, 2H).

I-57: yellow solid. ESI-MS (M+H)⁺: 435.8.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 8.67 (s, 2H), 8.46 (s, 1H),7.71-7.69 (m, 3H), 7.51 (d, J=8.4 Hz, 2H), 4.20-4.18 (m, 1H), 4.04-3.92(m, 2H), 3.70-3.61 (m, 2H), 3.38-3.35 (m, 2H).

I-58: yellow solid. ESI-MS (M+H)⁺: 435.0.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.21 (br s, 1H), 8.49-8.45 (m, 3H),7.69-7.66 (m, 4H), 7.49 (d, J=8.4 Hz, 2H), 7.40-7.37 (m, 1H), 4.31-4.29(m, 1H), 4.02-3.90 (m, 2H), 3.71-3.57 (m, 2H), 3.42-3.35 (m, 2H).

I-59: yellow solid. ESI-MS (M+H)⁺: 472.8.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.14 (br s, 1H), 11.26 (s, 1H), 8.39 (s,1H), 7.59 (s, 1H), 7.52-7.46 (m, 4H), 7.42 (d, J=8.0 Hz, 1H), 7.30 (s,1H), 7.09 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.13 (s, 1H),4.34-4.31 (m, 1H), 4.04-3.91 (m, 2H), 3.76-3.70 (m, 1H), 3.60-3.57 (m,1H), 3.43-3.38 (m, 2H).

I-60: white solid. ESI-MS (M+H)⁺: 446.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.43 (s, 1H), 7.67-7.62 (m, 3H), 7.49 (d,J=8.4 Hz, 2H), 7.36-7.26 (m, 5H), 3.91 (d, J=12.0 Hz, 1H), 3.74-3.71 (m,1H), 3.21-3.11 (m, 2H), 2.07-2.04 (m, 1H), 1.69-1.62 (m, 2H), 1.47-1.45(m, 1H), 1.17 (s, 3H).

I-61: yellow solid. ESI-MS (M+H)⁺: 448.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 8.64 (s, 2H), 8.46 (s, 1H),7.71-7.68 (m, 3H), 7.50 (d, J=8.4 Hz, 2H), 3.93 (d, J=12.0 Hz, 1H),3.78-3.75 (m, 1H), 3.26-3.16 (m, 2H), 2.07-2.05 (m, 1H), 1.71-1.64 (m,2H), 1.49-1.46 (m, 1H), 1.18 (s, 3H).

I-62: yellow solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.47-8.43 (m, 3H), 7.69-7.65 (m, 4H), 7.48(d, J=8.8 Hz, 2H), 7.38-7.35 (m, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.74-3.71(m, 1H), 3.25-3.13 (m, 2H), 2.07-2.03 (m, 1H), 1.69-1.64 (m, 2H),1.47-1.44 (m, 1H), 1.16 (s, 3H).

I-63: green solid. ESI-MS (M+H)⁺: 485.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H),7.51-7.45 (m, 4H), 7.40 (d, J=8.0 Hz, 1H), 7.29-7.28 (m, 1H), 7.08 (t,J=7.6 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.13 (s, 1H), 3.94 (d, J=12.0 Hz,1H), 3.77-3.74 (m, 1H), 3.23-3.12 (m, 2H), 2.08-2.05 (m, 1H), 1.72-1.64(m, 2H), 1.48-1.43 (m, 1H), 1.19 (s, 3H).

Synthesis of 2.1

To a solution of 1-(4-bromophenyl)ethanone (12 g, 60.6 mmol) indioxane/H₂O (120 mL, 10/1)) was added 4-fluorophenylboronic acid (12.7g, 90.9 mmol), Pd(dppf)Cl₂ (4.9 g, 6.06 mmol) and K₂CO₃ (25 g, 181.8mmol). The mixture was stirred at 80° C. for 16 h. After cooling to rt,the solvent was removed. The residue was purified by silica gelchromatography (PE/EA=100/1) to give compound 2.1 (12 g, Y: 92%) as awhite solid. ESI-MS (M+H)⁺: 215.1.

Synthesis of 2.2

To a solution of intermediate 2.1 (14 g, 65.4 mmol), CuBr₂ (29.2 g, 130mmol) and TsOH (1.23 g, 6.5 mmol) in EA (200 mL) was stirred at 80° C.for 16h. The mixture was cooled to rt, filtered, and the precipitatewashed with EA (200 mL), and the filtrate was concentrated to dryness.The crude product was purified by silica gel chromatography(PE/EA=200/1) to give compound 2.2 as a yellow solid (7 g, Y: 36%).ESI-MS (M+H)⁺: 293.1.

¹H NMR: (400 MHz, MeOD-d₄) δ: 8.12 (d, J=8.8, 2H), 7.80 (t, J=8.4, 2H),7.76-7.73 (m, 2H), 7.24 (d, 2H), 5.00 (s, 2H).

Synthesis of 2.3

A solution of 2.2 (7 g, 23.1 mmol) and sodium thiocyanate (9.3 g, 66.4mmol) in EtOH (60 mL) was stirred at 30° C. for 16 h. After cooling tort, ice-water was added. The solid was collected and dried to give thecompound 2.3 (5 g, Y: 78%) as a yellow solid. ESI-MS (M+H) 272.1.

¹H NMR: (400 MHz, MeOD-d₄) δ: 8.13 (d, J=8.8, 2H), 7.81 (t, J=8.4, 2H),7.76-7.75 (m, 2H), 7.27 (d, 2H), 5.25 (s, 2H).

Synthesis of 2.4

To a solution of compound 2.3 (1.7 g, 6.3 mmol) and ethyl2-(aminomethyl) pentanoate (1.2 g, 7.5 mmol) in t-BuOH (50 mL) was addedAcOH (5 mL). The mixture was stirred at 70° C. for 16 h. The solvent wasremoved. The residue was purified by silica gel chromatography(PE/EA=10/1) to give the desired compound 2.4 (1.7 g, Y: 63%) as ayellow solid. ESI-MS (M+H)⁺: 413.1.

Synthesis of 2.5

To a solution of compound 2.4 (1.7 g, 4.1 mmol) in AcOH (50 mL) wasadded bromine (650 mg, 4.1 mmol) portion wise. The resulting mixture wasstirred at rt for 5 min. The reaction mixture was quenched with water(100 mL), adjusted to pH 6-7 with NaHCO₃ (sat.), extracted with EA(3×100 mL). The combined organic layer was washed with brine (100 mL),dried and concentrated. The crude was purified through silica gelchromatography (PE/EA=10/1) to give the desired compound 2.5 (1.2 g, Y:60%) as a greenish solid. ESI-MS (M+H)⁺: 491.1.

Synthesis of I-87

To a solution of compound 2.4 (230 mg, 0.56 mmol) in MeOH (10 mL) wasadded LiOH (134 mg, 5.58 mmol) and water (1 mL). The mixture was stirredat 70° C. for 2 h. The solvent was removed. The residue was dissolved inwater (10 mL), adjusted to pH 5-6 with HCl (1N), extracted with DCM(3×10 mL). The combined organic layer was dried and concentrated. Thecrude was purified by prep-RPHPLC (MeCN/H₂O with 0.05% TFA as a mobilephase) to give the desired compound I-87 (180 mg, Y: 84%) as a whitesolid. ESI-MS (M+H)⁺: 385.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.91 (d, J=8.4 Hz, 2H), 7.77-7.72 (m, 3H),7.66 (d, J=8.8 Hz, 2H), 7.31-7.27 (m, 2H), 7.12 (s, 1H), 3.47-3.41 (m,2H), 2.74-2.71 (m, 1H), 1.54-1.49 (m, 2H), 1.39-1.33 (m, 2H), 0.90 (t,J=7.2 Hz, 3H).

Synthesis of I-88

To a solution of compound, I-87 (100 mg, 0.26 mmol) in AcOH (5 mL) wasadded bromine (40 mg, 0.26 mmol) portion wise. The resulting mixture wasstirred at rt for 5 min. The reaction mixture was quenched with water(10 mL), extracted with DCM (100 mL×3). The combined organic layer wasdried and concentrated. The crude was purified by prep-HPLC (MeCN/H₂Owith 0.05% TFA as a mobile phase) to give the desired compound I-88 (40mg, Y: 33%) as a white solid. ESI-MS (M+H)⁺: 464.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.32 (s, 1H), 8.00-7.94 (m, 3H),7.78-7.71 (m, 4H), 7.33-7.28 (m, 2H), 3.46-3.38 (m, 2H), 2.71-2.68 (m,1H), 1.52-1.47 (m, 2H), 1.37-1.30 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Synthesis of I-89-I-92 General Procedure for Suzuki Coupling

To a solution of compound, I-88 (1 eq) and aryl-boronic acid (1.5 eq) indioxane/H₂O (5/1) was added Pd(dppf)Cl₂ (0.1 eq) and K₃PO₄ (3 eq). Themixture was stirred at 80° C. for 16 h under N₂ protection. The solventwas removed. The residue was dissolved in MeOH (10 mL), added LiOH (10eq). The mixture was stirred at 70° C. for 2 h. The solvent was removed.The residue was dissolved in water (10 mL), adjusted pH to 5-6 with HCl(1N), extracted with DCM (10 mL×3). The combined organic layer was driedand concentrated. The crude was purified by prep-HPLC (MeCN/H₂O with0.05 FA as a mobile phase) to give the desired compounds I-89, I-90,I-91 and I-92.

I-64: white solid. ESI-MS (M+H)⁺: 385.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.18 (s, 1H), 7.90-7.88 (m, 2H),7.76-7.65 (m, 5H), 7.31-7.27 (m, 2H), 7.08 (s, 1H), 4.01-3.96 (m, 1H),2.44-2.40 (m, 2H), 1.99-1.97 (m, 1H), 0.94-0.90 (m, 6H).

I-65: white solid. ESI-MS (M+H)⁺: 463.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H), 7.94-7.87 (m, 3H),7.78-7.71 (m, 4H), 7.33-7.29 (m, 2H), 4.01-3.96 (m, 1H), 2.54-2.36 (m,2H), 1.96-1.93 (m, 1H), 0.92-0.90 (m, 6H).

I-66: white solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.23 (s, 1H), 7.75-7.69 (m, 3H),7.57-7.55 (m, 2H), 7.49-7.47 (m, 2H), 7.32-7.24 (m, 7H), 4.01-3.96 (m,1H), 2.54-2.40 (m, 2H), 2.01-1.96 (m, 1H), 0.94-0.92 (m, 6H).

I-67: white solid. ESI-MS (M+H)⁺: 463.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.03 (s, 1H), 8.64 (s, 2H), 8.07-8.05 (m,1H), 7.75-7.71 (m, 2H), 7.64-7.62 (m, 2H), 7.49-7.47 (m, 2H), 7.31-7.26(m, 2H), 4.01-3.96 (m, 1H), 2.54-2.40 (m, 2H), 1.99-1.97 (m, 1H),0.94-0.92 (m, 6H).

I-68: white solid. ESI-MS (M+H)⁺: 462.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.43 (m, 2H), 7.92-7.90 (m, 1H),7.73-7.70 (m, 2H), 7.68-7.65 (m, 1H), 7.61-7.59 (m, 2H), 7.47-7.45 (m,2H), 7.37-7.33 (m, 1H), 7.30-7.25 (m, 2H), 4.01-3.96 (m, 1H), 2.54-2.44(m, 2H), 1.99-1.97 (m, 1H), 0.94-0.91 (m, 6H).

I-69: white solid. ESI-MS (M+H)⁺: 500.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.23 (s, 1H), 7.67-7.63 (m, 3H),7.47-7.45 (m, 4H), 7.38-7.21 (m, 4H), 7.07-7.03 (m, 1H), 6.94-6.92 (m,1H), 6.19-6.18 (m, 1H), 4.01-3.96 (m, 1H), 2.54-2.44 (m, 2H), 2.02-1.99(m, 1H), 0.96-0.93 (m, 6H).

I-70: white solid. ESI-MS (M+H)⁺: 371.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.33 (s, 1H), 7.91-7.89 (m, 2H),7.75-7.60 (m, 5H), 7.32-7.27 (m, 2H), 7.09 (s, 1H), 3.52-3.50 (m, 2H),1.18 (s, 6H).

I-71: white solid. ESI-MS (M+H)⁺: 449.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 7.95-7.93 (m, 2H),7.84-7.71 (m, 5H), 7.33-7.29 (m, 2H), 3.49-3.47 (m, 2H), 1.16 (s, 6H).

I-72: yellow solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.73-7.63 (m, 3H), 7.597-7.57 (m, 2H),7.51-7.49 (m, 2H), 7.34-7.25 (m, 7H), 2.94 (s, 2H), 1.50 (s, 6H).

I-73: white solid. ESI-MS (M+H)⁺: 449.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 8.67 (s, 2H), 8.01 (brs,1H), 7.75-7.72 (m, 2H), 7.65-7.63 (m, 2H), 7.51-7.49 (m, 2H), 7.31-7.27(m, 2H), 2.91 (s, 2H), 1.50 (s, 6H).

I-74: white solid. ESI-MS (M+H)⁺: 448.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.43 (m, 2H), 7.83-7.82 (m, 1H),7.73-7.70 (m, 2H), 7.67-7.65 (m, 1H), 7.61-7.59 (m, 2H), 7.47-7.45 (m,2H), 7.37-7.34 (m, 1H), 7.30-7.26 (m, 2H), 3.50-3.49 (m, 2H), 1.18 (s,6H).

I-75: white solid. ESI-MS (M+H)⁺: 486.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.38 (s, 1H), 11.22 (s, 1H), 7.67-7.59(m, 3H), 7.47-7.45 (m, 4H), 7.38-7.21 (m, 4H), 7.08-7.04 (m, 1H),6.93-6.91 (m, 1H), 6.19-6.18 (m, 1H), 3.53-3.52 (m, 2H), 1.21 (s, 6H).

I-76: white solid. ESI-MS (M+H)⁺: 355.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.83 (s, 1H), 7.93-7.91 (m, 2H),7.76-7.67 (m, 4H), 7.38 (s, 1H), 7.32-7.28 (m, 2H), 4.27-4.23 (m, 2H),4.13-4.09 (m, 2H), 3.66-3.62 (m, 1H).

I-77: yellow solid. ESI-MS (M+H)⁺: 431.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.73-7.70 (m, 2H), 7.60-7.58 (m, 2H),7.49-7.47 (m, 2H), 7.36-7.26 (m, 7H), 4.30-4.26 (m, 2H), 4.15-4.12 (m,2H), 3.69-3.67 (m, 1H).

I-78: white solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 8.69 (s, 2H), 7.76-7.72 (m,2H), 7.66-7.64 (m, 2H), 7.49-7.47 (m, 2H), 7.32-7.27 (m, 2H), 4.34-4.27(m, 2H), 4.18-4.15 (m, 2H), 3.72-3.67 (m, 1H).

I-79: yellow solid. ESI-MS (M+H)⁺: 432.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.55 (s, 2H), 7.88-7.86 (m, 1H), 7.75-7.71(m, 2H), 7.64-7.62 (m, 2H), 7.55-7.47 (m, 3H), 7.31-7.27 (m, 2H),4.33-4.29 (m, 2H), 4.18-4.14 (m, 2H), 3.71-3.68 (m, 1H).

I-80: yellow solid. ESI-MS (M+H)⁺: 470.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.25 (s, 1H), 7.67-7.64 (m, 2H),7.48-7.31 (m, 6H), 7.26-7.22 (m, 2H), 7.10-7.06 (m, 1H), 6.96-6.94 (m,1H), 6.19 (s, 1H), 4.32-4.28 (m, 2H), 4.17-4.14 (m, 2H), 3.71-3.69 (m,1H).

I-81: white solid. ESI-MS (M+H)⁺: 369.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.93-7.91 (m, 2H), 7.76-7.72 (m, 2H),7.69-7.67 (m, 2H), 7.37 (s, 1H), 7.32-7.28 (m, 2H), 4.27-4.25 (m, 2H),3.89-3.87 (m, 2H), 1.54 (s, 3H).

I-82: white solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.99 (s, 1H), 7.94-7.92 (m, 2H),7.78-7.73 (m, 4H), 7.34-7.29 (m, 2H), 4.26-4.24 (m, 2H), 3.88-3.86 (m,2H), 1.53 (s, 3H).

I-83: yellow solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.96 (s, 1H), 7.73-7.70 (m, 2H),7.59-7.57 (m, 2H), 7.49-7.47 (m, 2H), 7.37-7.25 (m, 7H), 4.29-4.27 (m,2H), 3.91-3.89 (m, 2H), 1.55 (s, 3H).

I-84: yellow solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.09 (s, 1H), 9.07 (s, 1H), 8.68 (s, 2H),7.75-7.72 (m, 2H), 7.66-7.64 (m, 2H), 7.49-7.47 (m, 2H), 7.32-7.27 (m,2H), 4.30-4.32 (m, 2H), 3.93-3.91 (m, 2H), 1.55 (s, 3H).

I-85: white solid. ESI-MS (M+H)⁺: 446.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.53 (s, 2H), 7.81-7.79 (m, 1H), 7.75-7.71(m, 2H), 7.64-7.62 (m, 2H), 7.48-7.46 (m, 3H), 7.31-7.27 (m, 2H),4.31-4.29 (m, 2H), 3.94-3.92 (m, 2H), 1.56 (s, 3H).

I-86: yellow solid. ESI-MS (M+H)⁺: 484.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.07 (s, 1H), 11.27 (s, 1H), 7.67-7.64(m, 2H), 7.46-7.39 (m, 5H), 7.32-7.31 (m, 1H), 7.26-7.22 (m, 2H),7.09-7.06 (m, 1H), 6.96-6.94 (m, 1H), 6.19 (s, 1H), 4.30-4.28 (m, 2H),3.91-3.89 (m, 2H), 1.56 (s, 3H).

I-87: pale-white solid. ESI-MS (M+H)⁺: 385.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.92-7.89 (m, 2H), 7.77-7.72 (m, 3H),7.67-7.65 (m, 2H), 7.31-7.27 (m, 2H), 7.12 (s, 1H), 3.47-3.41 (m, 2H),2.74-2.71 (m, 1H), 1.54-1.49 (m, 2H), 1.39-1.33 (m, 2H), 0.90 (t, J=7.2Hz, 3H).

I-88: white solid. ESI-MS (M+H)⁺: 463.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.32 (s, 1H), 8.00-7.94 (m, 3H),7.78-7.71 (m, 4H), 7.33-7.28 (m, 2H), 3.46-3.38 (m, 2H), 2.71-2.68 (m,1H), 1.52-1.47 (m, 2H), 1.37-1.30 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

I-89: pale-white solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 7.88-7.85 (m, 1H),7.73-7.69 (m, 2H), 7.58-7.56 (m, 2H), 7.50-7.47 (m, 2H), 7.35-7.31 (m,2H), 7.28-7.25 (m, 5H), 3.51-3.33 (m, 2H), 2.75-2.72 (m, 1H), 1.55-1.49(m, 2H), 1.39-1.29 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

I-90: yellow solid. ESI-MS (M+H)⁺: 463.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.64 (s, 2H), 8.14 (brs,1H), 7.75-7.71 (m, 2H), 7.64-7.62 (m, 2H), 7.49-7.47 (m, 2H), 7.30-7.26(m, 2H), 3.50-3.48 (m, 2H), 2.73-2.70 (m, 1H), 1.54-1.48 (m, 2H),1.38-1.33 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

I-91: pale-white solid. ESI-MS (M+H)⁺: 462.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.45-8.43 (m, 2H), 8.08-8.01 (m, 1H),7.74-7.70 (m, 2H), 7.68-7.65 (m, 1H), 7.61-7.59 (m, 2H), 7.48-7.46 (m,2H), 7.38-7.34 (m, 1H), 7.29-7.25 (m, 2H), 3.49-3.43 (m, 2H), 2.76-2.72(m, 1H), 1.53-1.51 (m, 2H), 1.36-1.32 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

I-92: yellow solid. ESI-MS (M+H)⁺: 500.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 11.22 (s, 1H), 7.76 (brs,1H), 7.67-7.63 (m, 2H), 7.47-7.45 (m, 4H), 7.39-7.37 (m, 1H), 7.30-7.29(m, 1H), 7.25-7.20 (m, 2H), 7.08-7.04 (m, 1H), 6.94-6.92 (m, 1H),6.19-6.18 (m, 1H), 3.49-3.33 (m, 2H), 2.74-2.72 (m, 1H), 1.57-1.54 (m,2H), 1.38-1.35 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

I-93: white solid. ESI-MS (M+H)⁺: 357.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.29 (s, 1H), 7.91-7.89 (m, 2H),7.76-7.72 (m, 3H), 7.68-7.66 (m, 2H), 7.32-7.27 (m, 2H), 7.12 (s, 1H),4.10-4.06 (m, 1H), 2.69-2.65 (m, 1H), 2.40-2.36 (m, 1H), 1.25 (d, J=6.4Hz, 3H).

I-94: white solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.27 (s, 1H), 7.95-7.88 (m, 3H),7.78-7.72 (m, 4H), 7.33-7.29 (m, 2H), 4.11-4.07 (m, 1H), 2.65-2.60 (m,1H), 2.44-2.38 (m, 1H), 1.23 (d, J=6.4 Hz, 3H).

I-95: white solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.76-7.70 (m, 3H), 7.58-7.56 (m, 2H),7.50-7.48 (m, 2H), 7.35-7.25 (m, 7H), 4.00-3.97 (m, 1H), 2.44-2.43 (m,1H), 2.25-2.23 (m, 1H), 1.23 (d, J=6.4 Hz, 3H).

I-96: white solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.65 (s, 2H), 8.13 (brs,1H), 7.75-7.72 (m, 2H), 7.65-7.63 (m, 2H), 7.50-7.48 (m, 2H), 7.31-7.27(m, 2H), 4.12-4.10 (m, 1H), 2.61-2.51 (m, 1H), 2.43-2.37 (m, 1H), 1.26(d, J=6.4 Hz, 3H).

I-97: white solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 8.45-8.43 (m, 2H),7.91-7.89 (m, 1H), 7.73-7.59 (m, 5H), 7.48-7.46 (m, 2H), 7.37-7.25 (m,3H), 4.12-4.10 (m, 1H), 2.67-2.62 (m, 1H), 2.44-2.42 (m, 1H), 1.26 (d,J=6.4 Hz, 3H).

I-98: white solid. ESI-MS (M+H)⁺: 472.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 11.23 (s, 1H), 7.66-7.63(m, 3H), 7.47-7.37 (m, 5H), 7.31-7.21 (m, 3H), 7.08-7.04 (m, 1H),6.94-6.92 (m, 1H), 6.19 (s, 1H), 4.16-4.13 (m, 1H), 2.74-2.68 (m, 1H),2.45-2.39 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).

I-99: yellow solid. ESI-MS (M+H)⁺: 357.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.48 (s, 1H), 7.92-7.90 (m, 2H),7.79-7.72 (m, 3H), 7.68-7.66 (m, 2H), 7.32-7.27 (m, 2H), 7.13 (s, 1H),3.54-3.52 (m, 1H), 3.33-3.31 (m, 1H), 2.80-2.75 (m, 1H), 1.14 (d, J=6.8Hz, 3H).

I-100: yellow solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, CDCl₃) δ: 7.76-7.74 (m, 2H), 7.60-7.57 (m, 4H),7.16-7.11 (m, 2H), 3.51-3.45 (m, 1H), 3.19-3.16 (m, 1H), 2.87-2.82 (m,1H), 1.25 (d, J=7.2 Hz, 3H).

I-101: white solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 7.73-7.69 (m, 3H),7.58-7.56 (m, 2H), 7.50-7.48 (m, 2H), 7.33-7.25 (m, 7H), 3.44-3.31 (m,2H), 2.80-2.75 (m, 1H), 1.14 (d, J=6.8 Hz, 3H).

I-102: white solid. ESI-MS (M+H)⁺: 435.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 8.65 (s, 2H), 8.17 (brs,1H), 7.75-7.72 (m, 2H), 7.65-7.63 (m, 2H), 7.50-7.48 (m, 2H), 7.31-7.27(m, 2H), 3.56-3.54 (m, 2H), 2.80-2.78 (m, 1H), 1.14 (d, J=6.8 Hz, 3H).

I-103: yellow solid. ESI-MS (M+H)⁺: 434.1.

¹H NMR: (400 MHz, CD3OD) δ: 8.50-8.46 (m, 2H), 7.73-7.63 (m, 3H),7.59-7.57 (m, 2H), 7.51-7.49 (m, 2H), 7.38-7.35 (m, 1H), 7.21-7.16 (m,2H), 3.66-3.61 (m, 1H), 3.51-3.46 (m, 1H), 2.93-2.90 (m, 1H), 1.27 (d,J=6.8 Hz, 3H).

I-104: white solid. ESI-MS (M+H)⁺: 472.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.22 (s, 1H), 11.23 (s, 1H), 7.79-7.64(m, 3H), 7.46-7.21 (m, 7H), 7.08-7.05 (m, 1H), 6.94-6.92 (m, 1H), 6.55(s, 1H), 6.19 (s, 1H), 3.59-3.37 (m, 2H), 2.84-2.82 (m, 1H), 1.17 (d,J=6.8 Hz, 3H).

I-105: yellow solid. ESI-MS (M+H)⁺: 383.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 7.94-7.92 (m, 2H),7.76-7.72 (m, 2H), 7.69-7.67 (m, 2H), 7.33-7.28 (m, 3H), 4.05-4.01 (m,1H), 3.75-3.72 (m, 1H), 3.28-3.16 (m, 2H), 2.59-2.57 (m, 1H), 2.00-1.98(m, 1H), 1.77-1.57 (m, 3H).

I-106: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 7.73-7.69 (m, 2H),7.59-7.57 (m, 2H), 7.51-7.49 (m, 2H), 7.37-7.26 (m, 7H), 4.03-4.00 (m,1H), 3.71-3.68 (m, 1H), 3.29-3.18 (m, 2H), 2.53-2.51 (m, 1H), 2.00-1.98(m, 1H), 1.77-1.62 (m, 3H).

I-107: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 8.67 (s, 2H), 7.75-7.71 (m,2H), 7.65-7.63 (m, 2H), 7.50-7.48 (m, 2H), 7.31-7.27 (m, 2H), 4.05-4.01(m, 1H), 3.75-3.71 (m, 1H), 3.26-3.23 (m, 2H), 2.62-2.56 (m, 1H),2.02-1.99 (m, 1H), 1.79-1.59 (m, 3H).

I-108: yellow solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.55-8.54 (m, 2H),7.86-7.84 (m, 1H), 7.74-7.71 (m, 2H), 7.64-7.62 (m, 2H), 7.54-7.49 (m,3H), 7.31-7.27 (m, 2H), 4.04-4.02 (m, 1H), 3.73-3.70 (m, 1H), 3.35-3.23(m, 2H), 2.53-2.51 (m, 1H), 2.02-2.00 (m, 1H), 1.79-1.60 (m, 3H).

I-109: yellow solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.59 (s, 1H), 11.26 (s, 1H), 7.66-7.65(m, 2H), 7.47-7.31 (m, 6H), 7.26-7.24 (m, 2H), 7.08-7.06 (m, 1H),6.98-6.97 (m, 1H), 6.19 (s, 1H), 4.07-4.04 (m, 1H), 3.74-3.71 (m, 1H),3.31-3.24 (m, 2H), 2.53-2.51 (m, 1H), 2.02-2.00 (m, 1H), 1.79-1.64 (m,3H).

I-110: white solid. ESI-MS (M+H)⁺: 383.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.94-7.92 (m, 2H), 7.75-7.72 (m, 2H),7.68-7.66 (m, 2H), 7.31-7.27 (m, 2H), 7.23 (s, 1H), 4.25-4.21 (m, 1H),3.48-3.29 (m, 2H), 3.04-3.00 (m, 1H), 2.38-2.32 (m, 1H), 2.18-1.85 (m,4H).

I-111: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.45 (s, 1H), 7.73-7.70 (m, 2H),7.60-7.58 (m, 2H), 7.51-7.49 (m, 2H), 7.36-7.25 (m, 7H), 4.25-4.21 (m,1H), 3.48-3.29 (m, 2H), 3.04-3.01 (m, 1H), 2.43-2.40 (m, 1H), 2.18-1.90(m, 4H).

I-112: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 9.05 (s, 1H), 8.67 (s, 2H),7.77-7.72 (m, 2H), 7.67-7.64 (m, 2H), 7.51-7.49 (m, 2H), 7.32-7.27 (m,2H), 4.27-4.25 (m, 1H), 3.49-3.33 (m, 2H), 3.03-3.00 (m, 1H), 2.43-2.40(m, 1H), 2.20-1.89 (m, 4H).

I-113: yellow solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.55 (s, 1H), 8.48-8.46 (m, 1H), 7.56-7.47(m, 7H), 7.22-7.19 (m, 1H), 7.13-7.09 (m, 2H), 4.38-4.37 (m, 1H),3.57-3.54 (m, 1H), 3.43-3.37 (m, 1H), 3.12-3.07 (m, 1H), 2.67-2.62 (m,1H), 2.40-2.35 (m, 1H), 2.17-1.99 (m, 3H).

I-114: yellow solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 7.67-7.63 (m, 2H),7.49-7.38 (m, 5H), 7.31-7.20 (m, 3H), 7.08-7.05 (m, 1H), 6.95-6.93 (m,1H), 6.20 (s, 1H), 4.26-4.23 (m, 1H), 3.49-3.43 (m, 1H), 3.39-3.33 (m,1H), 3.08-3.05 (m, 1H), 2.41-2.35 (m, 1H), 2.21-1.86 (m, 4H).

I-115: white solid. ESI-MS (M+H)⁺: 369.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.61 (s, 1H), 7.95-7.93 (m, 2H),7.76-7.72 (m, 2H), 7.68-7.66 (m, 2H), 7.32-7.24 (m, 3H), 3.66-3.64 (m,2H), 3.51-3.47 (m, 2H), 3.28-3.24 (m, 1H), 2.29-2.20 (m, 2H).

I-116: white solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.73-7.70 (m, 2H), 7.59-7.57 (m, 2H),7.51-7.49 (m, 2H), 7.34-7.26 (m, 7H), 3.63-3.61 (m, 2H), 3.48-3.46 (m,2H), 3.28-3.25 (m, 1H), 2.24-2.22 (m, 2H).

I-117: yellow solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.65 (s, 1H), 9.05 (s, 1H), 8.66 (s, 2H),7.76-7.72 (m, 2H), 7.66-7.64 (m, 2H), 7.52-7.49 (m, 2H), 7.32-7.27 (m,2H), 3.68-3.67 (m, 2H), 3.53-3.50 (m, 2H), 3.31-3.28 (m, 1H), 2.32-2.23(m, 2H).

I-118: white solid. ESI-MS (M+H)⁺: 446.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.46-8.44 (m, 2H), 7.74-7.66 (m, 3H),7.63-7.60 (m, 2H), 7.49-7.47 (m, 2H), 7.38-7.35 (m, 1H), 7.30-7.26 (m,2H), 3.66-3.65 (m, 2H), 3.51-3.48 (m, 2H), 3.27-3.24 (m, 1H), 2.31-2.21(m, 2H).

I-119: white solid. ESI-MS (M+H)⁺: 484.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.25 (s, 1H), 7.67-7.64 (m, 2H),7.50-7.38 (m, 5H), 7.31-7.21 (m, 3H), 7.09-7.05 (m, 1H), 6.95-6.93 (m,1H), 6.19 (s, 1H), 3.68-3.66 (m, 2H), 3.58-3.56 (m, 2H), 3.27-3.25 (m,1H), 2.30-2.22 (m, 2H).

I-120: white solid. ESI-MS (M+H)⁺: 369.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.90-7.88 (m, 2H), 7.75-7.71 (m, 3H),7.66-7.64 (m, 2H), 7.31-7.26 (m, 2H), 7.08 (s, 1H), 3.53-3.51 (m, 2H),1.02-0.90 (m, 4H).

I-121: white solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.94-7.92 (m, 3H), 7.77-7.70 (m, 4H),7.33-7.28 (m, 2H), 3.49-3.47 (m, 2H), 1.04-0.91 (m, 4H).

I-122: white solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.26 (s, 1H), 7.81-7.69 (m, 3H),7.57-7.55 (m, 2H), 7.48-7.46 (m, 2H), 7.34-7.24 (m, 7H), 3.55-3.54 (m,2H), 1.10-1.03 (m, 4H).

I-123: yellow solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.41 (s, 1H), 9.03 (s, 1H), 8.64 (s, 2H),8.12 (brs, 1H), 7.75-7.71 (m, 2H), 7.64-7.62 (m, 2H), 7.48-7.46 (m, 2H),7.31-7.26 (m, 2H), 3.57-3.56 (m, 2H), 1.10-1.03 (m, 4H).

I-124: white solid. ESI-MS (M+H)⁺: 446.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.42 (m, 2H), 7.95-7.94 (m, 1H),7.73-7.64 (m, 3H), 7.61-7.59 (m, 2H), 7.46-7.44 (m, 2H), 7.37-7.25 (m,3H), 3.56-3.55 (m, 2H), 1.09-1.01 (m, 4H).

I-125: white solid. ESI-MS (M+H)⁺: 484.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.21 (s, 1H), 7.70-7.63 (m, 3H),7.44-7.36 (m, 5H), 7.29-7.20 (m, 3H), 7.08-7.04 (m, 1H), 6.93-6.91 (m,1H), 6.18 (s, 1H), 3.58-3.56 (m, 2H), 1.10-1.04 (m, 4H).

I-126: white solid. ESI-MS (M+H)⁺: 383.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.06 (brs, 1H), 7.91-7.89 (m, 2H),7.75-7.65 (m, 5H), 7.31-7.27 (m, 2H), 7.10 (s, 1H), 3.40-3.26 (m, 2H),3.10-2.92 (m, 1H), 2.61-2.55 (m, 1H), 2.28-2.20 (m, 2H), 2.02-1.89 (m,2H).

I-127: white solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.94-7.92 (m, 3H), 7.77-7.71 (m, 4H),7.33-7.29 (m, 2H), 3.34-3.27 (m, 2H), 3.08-2.90 (m, 1H), 2.61-2.55 (m,1H), 2.25-2.19 (m, 2H), 1.98-1.87 (m, 2H).

I-128: white solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.09 (s, 1H), 7.81-7.69 (m, 3H),7.57-7.55 (m, 2H), 7.49-7.47 (m, 2H), 7.32-7.25 (m, 7H), 3.39-3.24 (m,2H), 3.09-2.91 (m, 1H), 2.65-2.56 (m, 1H), 2.29-2.21 (m, 2H), 2.00-1.89(m, 2H).

I-129: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.09 (brs, 1H), 9.03 (s, 1H), 8.64 (s,2H), 8.13-8.08 (m, 1H), 7.75-7.71 (m, 2H), 7.64-7.62 (m, 2H), 7.49-7.47(m, 2H), 7.31-7.26 (m, 2H), 3.42-3.29 (m, 2H), 3.12-2.90 (m, 1H),2.61-2.54 (m, 1H), 2.29-2.21 (m, 2H), 2.02-1.87 (m, 2H).

I-130: white solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.43 (m, 2H), 7.98-7.93 (m, 1H),7.74-7.64 (m, 3H), 7.61-7.59 (m, 2H), 7.47-7.45 (m, 2H), 7.37-7.26 (m,3H), 3.41-3.27 (m, 2H), 3.09-2.89 (m, 1H), 2.62-2.54 (m, 1H), 2.29-2.20(m, 2H), 2.02-1.85 (m, 2H).

I-131: white solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.08 (s, 1H), 11.22 (s, 1H), 7.74-7.63(m, 3H), 7.45-7.36 (m, 5H), 7.30-7.20 (m, 3H), 7.07-7.04 (m, 1H),6.94-6.92 (m, 1H), 6.18 (s, 1H), 3.43-3.29 (m, 2H), 3.12-2.92 (m, 1H),2.62-2.57 (m, 1H), 2.31-2.26 (m, 2H), 2.03-1.90 (m, 2H).

I-136: white solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, CDCl₃) δ: 7.58-7.51 (m, 4H), 7.44-7.41 (m, 2H),7.33-7.24 (m, 5H), 7.12-7.07 (m, 2H), 4.05-4.02 (m, 2H), 3.21-3.14 (m,2H), 2.63-2.61 (m, 1H), 2.09-2.06 (m, 2H), 1.94-1.89 (m, 2H).

I-137: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, CDCl₃) δ: 9.03 (s, 1H), 8.63 (s, 2H), 7.55-7.48 (m,6H), 7.15-7.10 (m, 2H), 4.07-4.03 (m, 2H), 3.28-3.21 (m, 2H), 2.69-2.61(m, 1H), 2.12-2.08 (m, 2H), 1.97-1.86 (m, 2H).

I-138: yellow solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.58 (s, 1H), 8.47 (d, J=4.4 Hz, 1H), 7.60(d, J=8.0 Hz, 1H), 7.54-7.44 (m, 6H), 7.23-7.19 (m, 1H), 7.13-7.08 (m,2H), 4.06-4.03 (m, 2H), 3.24-3.18 (m, 2H), 2.63-2.60 (m, 1H), 2.10-2.08(m, 2H), 1.95-1.86 (m, 2H).

I-139: light yellow solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.20 (s, 1H), 7.56-7.54 (m, 2H), 7.49-7.45(m, 2H), 7.37-7.31 (m, 3H), 7.15-7.03 (m, 5H), 6.44 (s, 1H), 4.10-4.06(m, 2H), 3.22-3.16 (m, 2H), 2.65-2.62 (m, 1H), 2.13-2.09 (m, 2H),1.98-1.88 (m, 2H).

I-140: white solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.16 (s, 1H), 7.72-7.69 (m, 2H),7.59-7.57 (m, 2H), 7.51-7.49 (m, 2H), 7.38-7.25 (m, 7H), 4.33-4.30 (m,1H), 4.02-3.90 (m, 2H), 3.74-3.55 (m, 2H), 3.41-3.35 (m, 2H).

I-141: yellow solid. ESI-MS (M+H)⁺: 463.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.18 (s, 1H), 9.09 (s, 1H), 8.70 (s, 2H),7.75-7.71 (m, 2H), 7.65-7.63 (m, 2H), 7.51-7.49 (m, 2H), 7.31-7.27 (m,2H), 4.35-4.32 (m, 1H), 4.03-3.92 (m, 2H), 3.75-3.59 (m, 2H), 3.46-3.36(m, 2H).

I-142: white solid. ESI-MS (M+H)⁺: 462.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.49-8.48 (m, 2H), 7.73-7.70 (m, 3H),7.62-7.60 (m, 2H), 7.49-7.47 (m, 2H), 7.41-7.38 (m, 1H), 7.30-7.26 (m,2H), 4.30-4.28 (m, 1H), 4.00-3.91 (m, 2H), 3.71-3.57 (m, 2H), 3.46-3.38(m, 2H).

I-143: light yellow solid. ESI-MS (M+H)⁺: 500.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.26 (s, 1H), 7.65-7.62 (m, 2H),7.47-7.41 (m, 5H), 7.31-7.20 (m, 3H), 7.10-7.07 (m, 1H), 6.97-6.96 (m,1H), 6.19 (s, 1H), 4.25-4.23 (m, 1H), 4.08-3.95 (m, 2H), 3.71-3.60 (m,2H), 3.37-3.31 (m, 2H).

I-144: white solid. ESI-MS (M+H)⁺: 473.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.49 (s, 1H), 7.72-7.69 (m, 2H),7.58-7.56 (m, 2H), 7.50-7.48 (m, 2H), 7.35-7.25 (m, 7H), 3.92 (d, J=12.0Hz, 1H), 3.74-3.71 (m, 1H), 3.21-3.18 (m, 1H), 3.13 (d, J=12.4 Hz, 1H),2.07-2.03 (m, 1H), 1.73-1.60 (m, 2H), 1.47-1.43 (m, 1H), 1.18 (s, 3H).

I-145: yellow solid. ESI-MS (M+H)⁺: 475.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 8.67 (s, 2H), 7.75-7.71 (m,2H), 7.65-7.63 (m, 2H), 7.50-7.48 (m, 2H), 7.31-7.27 (m, 2H), 3.94 (d,J=12.4 Hz, 1H), 3.78-3.75 (m, 1H), 3.25-3.22 (m, 1H), 3.18 (d, J=12.8Hz, 1H), 2.08-2.05 (m, 1H), 1.73-1.60 (m, 2H), 1.50-1.44 (m, 1H), 1.18(s, 3H).

I-146: white solid. ESI-MS (M+H)⁺: 474.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.52 (s, 1H), 8.47-8.45 (m, 2H),7.73-7.67 (m, 3H), 7.62-7.60 (m, 2H), 7.48-7.46 (m, 2H), 7.39-7.36 (m,1H), 7.30-7.26 (m, 2H), 3.94 (d, J=12.8 Hz, 1H), 3.76-3.73 (m, 1H),3.32-3.23 (m, 1H), 3.19 (d, J=12.8 Hz, 1H), 2.08-2.04 (m, 1H), 1.73-1.60(m, 2H), 1.49-1.43 (m, 1H), 1.18 (s, 3H).

I-147: light yellow solid. ESI-MS (M+H)⁺: 512.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 7.66-7.63 (m, 2H),7.45-7.38 (m, 5H), 7.30-7.21 (m, 3H), 7.09-7.05 (m, 1H), 6.95-6.94 (m,1H), 6.18 (s, 1H), 3.95 (d, J=12.4 Hz, 1H), 3.76-3.72 (m, 1H), 3.23-3.18(m, 1H), 3.13 (d, J=12.0 Hz, 1H), 2.09-2.05 (m, 1H), 1.71-1.61 (m, 2H),1.47-1.42 (m, 1H), 1.19 (s, 3H).

Synthesis of 3.1

A solution of 1-(4-phenoxyphenyl) ethan-1-one (2.0 g, 9.0 mmol), CuBr₂(2.1 g, 9.1 mmol) and TsOH (162 mg, 0.9 mmol) in EA (20 mL) was stirredat 80° C. for 16h. T mixture was cooled to rt and filtered. Theprecipitate was washed with EA (200 mL). The filtrate was concentratedand. the crude product was purified by silica gel chromatography(PE/EA=200/1) to give compound 3.1 as a yellow solid (1.2 g, Y: 44%).ESI-MS (M+H)⁺: 291.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.03 (d, J=8.8, 2H), 7.47 (t, J=7.6, 2H),7.28-7.25 (m, 1H), 7.15 (d, J=7.6, 2H), 7.15 (d, J=8.8, 2H), 4.87 (s,2H).

Synthesis of 3.2

A solution of 3.1 (1.2 g, 4.1 mmol) and sodium thiocyanate (402 mg, 4.96mmol) in EtOH (15 mL) was stirred at 30° C. for 16 h. After cooling tort, ice-water was added. The solid was collected and dried to give thecompound 3.2 (1.0 g, Y: 90%) as a yellow solid. ESI-MS (M+H)⁺: 270.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.04 (d, J=8.8, 2H), 7.48 (t, J=8, 2H),7.29 (t, J=8, 1H), 7.15 (d, 2H), 7.08 (d, J=8.8, 2H), 5.07 (s, 2H).

Synthesis of 3.3

To a solution of compound 3.2 (2.5 g, 9.2 mmol) and amine (1.54 g, 9.2mmol) in EtOH (120 mL) was added NaHCO₃ (1.56 g, 18.6 mmol). The mixturewas stirred at 50° C. for 16 h. The solvent was removed and the residuepurified by silica gel chromatography (PE/EA=10/1) to give the desiredcompound 3.3 (1.7 g, Y: 48%) as a yellow solid. ESI-MS (M+H)⁺: 381.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.84 (d, J=8.8, 2H), 7.34 (t, J=8, 2H),7.13-7.10 (m, 5H), 3.70 (s, 3H), 3.51 (d, J=6.4, 2H), 5.07 (s, 2H),1.33-1.30 (m, 2H), 1.27-1.24 (m, 2H).

Synthesis of 3.4

To a solution of compound 3.3 (1.7 g, 4.5 mmol) in THF (85 mL) was addedNBS (396 mg, 2.2 mmol) portion wise. The resulting mixture was stirredat rt for 20 min. The reaction mixture was concentrated to give thecrude, which was purified by silica gel chromatography (PE/EA=10/1) togive the desired compound 3.4 (1.14 g, Y: 57%) as a yellow solid. ESI-MS(M+H)⁺: 459.1.

Synthesis of I-196-I-199

To a solution of compound 3.4 (285 mg, 1.0 eq) and aryl-boronic acid(1.5 eq) in dioxane/H₂O (10/1) was added Pd(dppf)Cl₂ (0.1 eq) and K₃PO₄(3 eq). The mixture was stirred at 80° C. for 16 h under N₂ atmosphere.The solvent was removed. The residue was dissolved in MeOH/H₂O (5:1; 5mL), and LiOH (5.0 eq) added. The mixture was stirred at rt for 16 h.The solvent was removed. The residue was dissolved in water (10 mL), pHadjusted to 5-6 with aq. HCl (1N), extracted with EA (10 mL×3). Thecombined organic layer was dried and concentrated. The crude waspurified by prep-RPHPLC (MeCN/H₂O with 0.05% TFA as mobile phase) togive the desired compounds I-196, I-197, I-198 & I-199.

I-148: white solid. ESI-MS (M+H)⁺: 383.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.2 (s, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.62(d, J=7.6 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.01(t, J=9.2 Hz, 4H), 6.92 (s, 1H), 4.92 (s, 1H), 2.46-2.41 (m, 2H),1.92-1.91 (m, 1H), 0.92-0.88 (m, 6H).

I-149: white solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.30 (s, 1H), 7.72 (d, J=8.4 Hz, 1H),7.32-7.26 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 2H), 6.88(d, J=8.8 Hz, 2H), 3.94 (s, 1H), 2.49-2.41 (m, 2H), 1.99-1.96 (m, 1H),0.93-0.90 (m, 6H).

I-150: white solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.31 (s, 1H), 9.00 (s, 1H), 8.60 (s, 2H),8.03 (d, J=8.4 Hz, 1H), 7.41 (t, J=6.0 Hz, 4H), 7.18-6.93 (m, 5H), 3.98(s, 1H), 2.50-2.49 (m, 1H), 1.97-1.95 (m, 1H), 0.93-0.90 (m, 6H).

I-151: white solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.44-8.39 (m, 2H), 7.91-7.89 (m, 1H),7.63-7.60 (m, 1H), 7.42-7.31 (m, 5H), 7.15 (t, J=8.4 Hz, 2H), 7.13-7.03(m, 2H), 6.93-6.90 (m, 2H), 3.92 (s, 1H), 2.49-2.40 (m, 2H), 1.98-1.96(m, 1H), 0.93-0.90 (m, 6H.

I-152: white solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 7.60 (d, J=8.4 Hz, 1H),7.37-7.28 (m, 6H), 7.12-6.78 (m, 5H), 6.77 (d, J=8.8 Hz, 2H), 6.12 (s,1H), 3.97-3.95 (m, 1H), 2.49-2.32 (m, 2H), 2.03-2.00 (m, 1H), 0.95-0.92(m, 6H).

I-153: white solid. ESI-MS (M+H)⁺: 369.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.84-7.81 (m, 2H), 7.60-7.58 (m, 1H),7.41-7.37 (m, 2H), 7.14 (t, J=7.2 Hz, 2H), 6.94 (s, 1H), 3.47-3.46 (m,2H), 1.15 (s, 6H).

I-154: yellow solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.68-7.65 (m, 1H), 7.41-7.37 (m, 4H),7.33-7.29 (m, 2H), 7.25-7.21 (m, 3H), 7.16-7.12 (t, J=8.0 Hz, 2H), 7.02(d, J=8.0 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H), 3.47-3.46 (m, 2H), 1.17 (s,6H).

I-155: white solid. ESI-MS (M+H)⁺: 447.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.01 (s, 1H), 8.61 (s, 2H), 7.97 (br s,1H), 7.43-7.40 (m, 4H), 7.19-7.15 (m, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.95(d, J=8.0 Hz, 2H), 3.51-3.50 (m, 2H), 1.17 (s, 6H).

I-156: white solid. ESI-MS (M+H)⁺: 446.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.41-8.39 (m, 2H), 7.85 (br s, 1H),7.62-7.60 (m, 1H), 7.40-7.33 (m, 5H), 7.15 (t, J=6.8 Hz, 2H), 7.04 (d,J=8.0 Hz, 2H), 6.91 (d, J=8.8 Hz, 1H), 3.43-3.31 (m, 2H), 1.15 (s, 6H).

I-157: white solid. ESI-MS (M+H)⁺: 486.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.20 (s, 1H), 7.54 (s, 1H), 7.38-7.33 (m,5H), 7.28 (s, 1H), 7.12-7.02 (m, 2H), 6.95-6.90 (m, 3H), 6.77 (d, J=8.8Hz, 2H), 6.12 (s, 1H), 3.51 (s, 2H), 1.17 (s, 6H).

I-158: white solid. ESI-MS (M+H)⁺: 429.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.41-7.38 (m, 4H), 7.35-7.31 (m, 2H),7.29-7.25 (m, 3H), 7.17-7.13 (m, 1H), 7.04-7.01 (m, 2H), 6.90 (d, J=8.8Hz, 1H), 2.23 (t, J=8.0 Hz, 2H), 4.11-4.07 (m, 2H), 3.65-3.57 (m, 1H).

I-159: white solid. ESI-MS (M+H)⁺: 431.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.40 (t, J=6.8 Hz, 4H), 7.33 (t, J=6.8 Hz,2H), 7.29-7.25 (m, 3H), 7.17-7.123 (m, 1H), 7.04-7.01 (m, 2H), 6.90 (d,J=8.8 Hz, 2H), 4.23 (t, J=8.4 Hz, 2H), 4.11-4.07 (m, 2H), 3.65-3.57 (m,1H).

I-160: white solid. ESI-MS (M+H)⁺: 430.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.55-8.51 (m, 2H), 7.86-7.84 (m, 1H),7.56-7.53 (m, 1H), 7.43-7.39 (m, 4H), 7.19-7.15 (m, 1H), 7.06-6.96 (m,2H), 6.95-6.92 (m, 2H), 4.31-4.27 (m, 2H), 4.16-3.12 (m, 2H), 3.70-3.64(m, 1H).

I-161: white solid. ESI-MS (M+H)⁺: 468.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.24 (s, 1H), 8.31 (s, 1H), 7.37-7.33 (m,5H), 7.31-7.29 (m, 1H), 7.12-7.03 (m, 2H), 6.95-6.91 (m, 3H), 6.79-6.77(m, 2H), 6.12 (s, 1H), 6.22-6.10 (m, 4H), 3.49-3.44 (m, 1H).

I-162: pale-white solid. ESI-MS (M+H)⁺: 367.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.88 (s, 1H), 7.84 (d, J=8.8 Hz, 2H),7.61 (t, J=7.6 Hz, 2H), 7.21 (s, 1H), 7.15-7.13 (m, 1H), 7.04-7.00 (m,4H), 4.23 (d, J=7.6 Hz, 2H), 3.86 (d, J=7.6 Hz, 2H), 1.54 (s, 3H).

I-163: white solid. ESI-MS (M+H)⁺: 443.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 13.12 (s, 1H), 7.42-7.35 (m, 4H),7.35-7.31 (m, 2H), 7.28-7.24 (m, 3H), 7.15 (t, J=7.6 Hz, 1H), 7.17-7.01(m, 2H), 6.92-6.88 (m, 2H), 4.23 (d, J=7.6 Hz, 2H), 3.86 (d, J=7.6 Hz,2H), 1.54 (s, 3H).

I-164: pale-white solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.95 (s, 1H), 9.04 (s, 1H), 8.64 (m, 2H),7.43-7.39 (m, 4H), 7.19-7.15 (m, 1H), 7.07-7.04 (m, 2H), 6.96-6.94 (m,2H), 4.29 (d, J=8.0 Hz, 2H), 3.92 (d, J=8.0 Hz, 2H), 1.55 (s, 3H).

I-165: yellow solid. ESI-MS (M+H)⁺: 444.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.52-8.49 (m, 2H), 7.81-7.78 (m, 2H),7.51-7.48 (m, 1H), 7.43-7.38 (m, 4H), 7.17 (t, J=7.6 Hz, 1H), 7.06-7.04(m, 2H), 7.04-6.92 (m, 2H), 4.29 (d, J=8.0 Hz, 2H), 3.92 (d, J=8.0 Hz,2H), 1.55 (s, 3H).

I-166: pale-white solid. ESI-MS (M+H)⁺: 482.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.23 (s, 1H), 7.38-7.30 (m, 6H),7.12-7.04 (m, 2H), 6.96-6.92 (m, 3H), 6.80-6.77 (m, 2H), 6.13 (s, 1H),4.27 (d, J=8.0 Hz, 2H), 3.89 (d, J=7.6 Hz, 2H), 1.56 (s, 3H).

I-167: yellow solid. ESI-MS (M+H)⁺: 383.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.78-7.78 (m, 2H), 7.73 (s, 1H), 7.41-7.37(m, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.04-6.96 (m, 5H), 3.37-3.35 (m, 1H),3.34-3.32 (m, 1H), 2.67-2.65 (m, 1H), 1.49-1.47 (m, 2H), 1.35-1.31 (m,2H), 0.90-0.86 (m, 3H).

I-168: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.82 (s, 1H), 7.41-7.37 (m, 4H), 7.32-7.29(m, 2H), 7.25-7.32 (m, 3H), 7.14 (t, J=7.6 Hz, 5H), 7.03 (d, J=7.6 Hz,2H), 6.88 (d, J=8.4 Hz, 1H), 3.43-3.32 (m, 2H), 2.67-2.64 (m, 1H),1.51-1.28 (m, 4H), 0.88 (t, J=7.2 Hz, 3H).

I-169: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 8.60 (s, 1H), 8.12 (s, 1H),7.43-7.39 (m, 4H), 7.16 (t, J=7.6 Hz, 1H), 7.0-7.04 (m, 2H), 6.96-6.93(m, 2H), 3.47-3.41 (m, 2H), 2.69-2.67 (m, 1H), 1.51-1.28 (m, 4H), 0.88(t, J=7.2 Hz, 3H).

I-170: yellow solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.47-8.41 (m, 2H), 7.47 (s, 1H), 7.32-7.26(m, 4H), 7.14-7.10 (m, 2H), 7.10-7.00 (m, 2H), 6.86-6.82 (m, 2H),3.55-3.48 (m, 1H), 3.23-3.21 (m, 1H), 2.79-2.77 (m, 1H), 1.68-1.25 (m,4H), 0.88 (t, J=7.2 Hz, 3H).

I-171: yellow solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 7.73 (s, 1H), 7.38-7.33 (m,5H), 7.30-7.28 (m, 1H), 7.12-7.03 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 6.12(s, 1H), 3.46-3.37 (m, 2H), 2.69-2.67 (m, 1H), 1.54-1.33 (m, 4H), 0.90(t, J=7.2 Hz, 3H).

I-172: yellow solid. ESI-MS (M+H)⁺: 431.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.34 (s, 1H), 7.72-7.70 (m, 1H),7.41-7.37 (m, 4H), 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 7.16-7.13 (m,1H), 7.03 (d, J=8.4 Hz, 2H), 6.90-6.88 (m, 2H), 4.07 (s, 1H), 2.66-2.51(m, 1H), 2.41-2.36 (m, 1H), 1.23 (d, J=6.8 Hz, 3H).

I-173: yellow solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.01 (s, 1H), 8.60 (s, 1H), 8.04-8.02 (m,1H), 7.43-7.38 (m, 4H), 7.18-7.15 (m, 1H), 7.07-7.05 (m, 2H), 6.96-6.93(m, 2H), 4.10-4.08 (m, 1H), 2.65-2.59 (m, 1H), 2.43-2.38 (m, 1H), 1.24(d, J=6.4 Hz, 3H).

I-174: yellow solid. ESI-MS (M+H)⁺: 432.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.42-8.39 (m, 2H), 7.89-7.86 (m, 1H),7.63-7.60 (m, 1H), 7.42-7.32 (m, 5H), 7.17-7.14 (m, 1H), 7.04 (d, J=8.8Hz, 2H), 4.09-4.06 (m, 1H), 2.65-2.59 (m, 1H), 2.42-2.36 (m, 1H), 1.23(d, J=6.4 Hz, 3H).

I-175: yellow solid. ESI-MS (M+H)⁺: 470.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 7.66 (s, 1H), 7.38-7.29 (m,6H), 7.10-7.03 (m, 2H), 6.96-6.93 (m, 3H), 6.77 (d, J=8.8 Hz, 2H), 6.12(s, 1H), 4.09 (s, 1H), 2.66-2.63 (m, 1H), 1.26 (d, J=6.4 Hz, 3H).

I-176: yellow solid. ESI-MS (M+H)⁺: 355.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.84-7.82 (m, 2H), 7.75 (s, 1H), 7.42-7.37(m, 2H), 7.14 (d, J=7.2 Hz, 1H), 7.04-6.97 (m, 5H), 3.53-3.49 (m, 1H),3.31-3.27 (m, 1H), 2.79-2.74 (m, 1H), 1.12 (d, J=7.2 Hz, 3H).

I-177: yellow solid. ESI-MS (M+H)⁺: 431.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.84-7.82 (m, 1H), 7.41-7.37 (m, 4H),7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 7.14 (t, J=7.2 Hz, 1H). 7.03 (d,J=7.6 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.50-3.46 (m, 2H), 2.73-2.70 (m,1H), 1.12 (d, J=7.2 Hz, 3H).

I-178: yellow solid. ESI-MS (M+H)⁺: 433.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 8.60 (s, 2H), 8.14 (s, 1H),7.43-7.39 (m, 4H), 7.14 (t, J=7.2 Hz, 1H), 7.07-7.04 (m, 2H), 6.95-6.93(m, 2H), 3.51-3.49 (m, 1H), 3.35-3.32 (m, 1H), 2.73-2.70 (m, 1H), 1.12(d, J=7.2 Hz, 3H).

I-179: yellow solid. ESI-MS (M+H)⁺: 432.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.46-8.44 (m, 1H), 8.44-8.42 (m, 1H),7.50-7.48 (m, 1H), 7.37-7.26 (m, 4H), 7.19-7.12 (m, 2H), 7.01-7.03 (m,2H). 6.91-6.88 (m, 2H), 36.89 (d, J=8.8, 2H), 3.50-3.46 (m, 2H),2.73-2.70 (m, 1H), 1.27 (d, J=6.8 Hz, 3H).

I-180: yellow solid. ESI-MS (M+H)⁺: 470.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 7.71 (s, 1H), 7.38-7.34 (m,5H), 7.30-7.28 (m, 1H), 7.12-7.03 (m, 2H), 6.99-6.76 (m, 3H), 6.77 (d,J=8.8 Hz, 2H), 6.12 (s, 1H), 3.53-3.51 (m, 2H), 2.76-2.74 (m, 1H), 1.14(d, J=6.8 Hz, 3H).

I-181: yellow solid. ESI-MS (M+H)⁺: 381.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.86 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.0 Hz,2H), 7.17-7.04 (m, 2H), 7.04-7.00 (m, 4H), 4.03-3.99 (m, 1H), 3.73-3.70(m, 1H), 3.25-3.13 (m, 2H), 2.51-2.49 (m, 1H), 2.07-1.97 (m, 1H),1.76-1.73 (m, 1H), 1.64-1.56 (m, 2H).

I-182: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.50 (s, 1H), 7.42-7.32 (m, 4H),7.28-7.27 (m, 2H), 7.26-7.24 (m, 3H), 7.17-7.13 (m, 1H), 7.08-7.04 (m,2H), 7.02-6.90 (m, 2H), 4.01-3.99 (m, 1H), 3.69-3.66 (m, 1H), 3.34-3.16(m, 2H), 2.51-2.49 (m, 1H), 2.01-1.98 (m, 1H), 1.76-1.75 (m, 1H),1.69-1.58 (m, 2H).

I-183: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.10 (s, 1H), 8.64 (s, 2H), 7.43-7.39 (m,4H), 7.19-7.15 (m, 1H), 7.06 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H),4.02-4.0 (m, 1H), 3.74-3.71 (m, 1H), 3.31-3.26 (m, 2H), 2.56-2.55 (m,1H), 2.00-1.99 (m, 1H), 1.77-1.61 (m, 3H).

I-184: yellow solid. ESI-MS (M+H)⁺: 458.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.75 (s, 1H), 8.45-8.43 (m, 2H),7.43-7.41 (m, 1H), 7.39-7.16 (m, 4H), 7.09-7.06 (m, 2H), 6.94-6.92 (m,2H), 4.02-4.00 (m, 1H), 3.71-3.68 (m, 1H), 3.30-3.18 (m, 2H), 2.58-2.50(m, 1H), 2.01-1.99 (m, 1H), 1.76-1.61 (m, 3H).

I-185: yellow solid. ESI-MS (M+H)⁺: 496.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.75 (s, 1H), 11.20 (s, 1H), 7.31-7.40(m, 6H), 7.13-7.05 (m, 2H), 6.96-6.94 (m, 3H), 6.80-6.78 (m, 2H), 6.13(s, 1H), 4.05-4.03 (m, 1H), 3.72-3.69 (m, 1H), 3.29-3.19 (m, 2H),2.61-2.50 (m, 1H), 2.07-1.97 (m, 1H), 1.77-1.76 (m, 1H), 1.67-1.62 (m,2H).

I-186: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.39-7.31 (m, 4H), 7.26-7.22 (m, 5H),7.13-7.09 (m, 1H), 7.04-7.02 (m, 2H), 6.90-6.88 (m, 2H), 4.37-4.32 (m,1H), 3.55-3.49 (m, 1H), 3.38-3.32 (m, 1H), 3.09-3.04 (m, 1H), 2.63-2.58(m, 1H), 2.37-2.31 (m, 1H), 2.13-2.09 (m, 2H), 1.98-1.94 (m, 1H).

I-187: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.01 (s, 1H), 8.61 (s, 2H), 7.43-7.39 (m,4H), 7.16 (t, J=7.2 Hz, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.96 (d, J=7.6 Hz,2H), 4.27-4.18 (m, 1H), 3.49-3.44 (m, 2H), 2.99-2.94 (m, 1H), 2.42-2.36(m, 1H), 2.21-2.05 (m, 2H), 2.00-1.85 (m, 2H).

I-188: yellow solid. ESI-MS (M+H)⁺: 458.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.52 (s, 1H), 8.45-8.44 (m, 1H), 7.52 (d,J=7.6 Hz, 1H), 7.37-7.32 (m, 4H), 7.20-7.17 (m, 1H), 7.14-7.10 (m, 1H),7.05-7.03 (m, 2H), 6.91-6.89 (m, 2H), 4.39-4.33 (m, 1H), 3.58-3.52 (m,1H), 3.42-3.33 (m, 1H), 3.11-3.06 (m, 1H), 2.64-2.57 (m, 1H), 2.38-2.11(m, 1H), 2.06-1.95 (m, 1H).

I-189: yellow solid. ESI-MS (M+H)⁺: 496.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.34 (s, 1H), 11.20 (s, 1H), 7.39-7.33(m, 5H), 7.30-7.29 (m, 1H), 7.12-7.03 (m, 2H), 6.96-6.91 (m, 3H),6.80-6.78 (m, 2H), 6.13 (s, 1H), 4.27-4.21 (m, 1H), 3.48-3.43 (m, 1H),3.36-3.35 (m, 1H), 3.08-3.04 (m, 1H), 2.43-2.37 (m, 1H), 2.16-1.84 (m,4H).

I-190: yellow solid. ESI-MS (M+H)⁺: 367.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.87-7.85 (m, 2H), 7.42-7.38 (m, 2H),7.16-7.13 (m, 1H), 7.09 (s, 1H), 7.04-7.00 (m, 4H), 3.64-3.61 (m, 2H),3.48-3.44 (m, 2H), (s, 1H), 3.26-3.22 (m, 1H), 2.25-2.20 (m, 2H).

I-191: yellow solid. ESI-MS (M+H)⁺: 443.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.42-7.40 (m, 4H), 7.37 (s, 1H), 7.34-7.30(m, 2H), 7.26-7.23 (m, 3H), 7.15 (t, J=7.2 Hz, 1H), 7.03 (d, J=7.6 Hz,2H), 6.90 (d, J=8.4 Hz, 2H), 3.63-3.61 (m, 2H), 3.48-3.44 (m, 2H),3.28-3.23 (m, 1H), 2.29-2.18 (m, 2H).

I-192: yellow solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.02 (s, 1H), 8.62 (s, 2H), 7.44-7.39 (m,4H), 7.17 (t, J=7.6 Hz, 1H), 7.07-7.05 (m, 2H), 6.97-6.95 (m, 2H),3.67-3.65 (m, 2H), 3.51-3.48 (m, 2H), 3.32-3.25 (m, 1H), 2.32-2.20 (m,2H).

I-193: yellow solid. ESI-MS (M+H)⁺: 444.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.63 (s, 1H), 8.43-8.41 (m, 2H),7.64-7.62 (m, 1H), 7.42-7.33 (m, 5H), 7.16 (t, J=7.2 Hz, 1H), 7.05-7.03(m, 2H), 6.94-6.92 (m, 2H), 3.68-3.60 (m, 2H), 3.50-3.46 (m, 2H),3.33-3.24 (m, 1H), 2.33-2.17 (m, 2H).

I-194: yellow solid. ESI-MS (M+H)⁺: 482.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.25 (s, 1H), 7.40-7.34 (m, 4H), 7.30 (m,1H), 7.09-7.05 (m, 2H), 6.96-6.94 (m, 2H), 6.80-6.78 (m, 2H), 6.13 (s,1H), 4.27 (s, 1H), 3.66-3.64 (m, 2H), 3.50-3.46 (m, 2H), 2.26-2.22 (m,2H).

I-195: yellow solid. ESI-MS (M+H)⁺: 367.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.82-7.78 (m, 2H), 7.66-7.64 (m, 1H),7.39-7.37 (m, 2H), 7.16-7.10 (m, 1H), 7.03-6.92 (m, 5H), 3.64-3.58 (s,2H), 1.06 (s, 2H), 1.98 (s, 2H).

I-196: yellow solid. ESI-MS (M+H)⁺: 443.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.77 (s, 1H), 7.44-7.37 (m, 4H), 7.32-7.29(m, 2H), 7.25-7.20 (m, 3H), 7.16 (t, J=13.6 Hz, 1H), 7.03-7.00 (m, 2H),6.89-6.87 (m, 2H), 3.51-3.47 (s, 2H), 1.11-1.04 (s, 2H), 1.00-0.96 (s,2H).

I-197: yellow solid. ESI-MS (M+H)⁺: 445.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.40 (s, 1H), 9.00 (s, 1H), 8.59 (s, 2H),8.09 (s, 1H), 7.43-7.38 (m, 4H), 7.16 (t, J=7.6 Hz, 1H), 7.06-7.04 (m,2H), 6.95-6.93 (m, 2H), 3.55-3.54 (s, 2H), 1.10-1.09 (s, 2H), 1.01-1.00(s, 2H).

I-198: yellow solid. ESI-MS (M+H)⁺: 444.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.41-8.39 (m, 2H), 7.90 (m, 1H), 7.62-7.60(m, 1H), 7.42-7.31 (m, 5H), 7.15 (t, J=7.2 Hz, 1H), 7.04 (d, J=8.0 Hz,2H), 6.95-6.93 (d, J=8.8 Hz, 2H), 3.52-3.47 (s, 2H), 1.60 (s, 2H), 0.95(s, 2H).

I-199: yellow solid. ESI-MS (M+H)⁺: 482.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.18 (s, 1H), 7.66 (s, 1H), 7.36-7.33 (m,5H), 7.29 (s, 1H), 7.12-7.02 (m, 2H), 6.95-6.89 (m, 3H), 6.77 (d, J=8.8Hz, 2H), 6.12 (s, 1H), 3.54 (s, 2H), 1.09 (s, 2H), 1.01 (s, 2H).

I-200: yellow solid. ESI-MS (M+H)⁺: 381.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.82 (d, J=8.8 Hz, 2H), 7.70-7.66 (m, 1H),7.42-7.38 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.04-6.95 (m, 5H), 7.37-3.33(m, 1H), 3.26-3.23 (m, 1H), 3.06-2.89 (m, 1H), 2.60-2.51 (m, 1H),2.25-2.18 (m, 2H), 1.98-1.83 (m, 2H).

I-201: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.00 (s, 1H), 7.80-7.73 (m, 1H),7.41-7.37 (m, 4H), 7.32-7.29 (m, 2H), 7.25-7.22 (m, 3H), 7.06-7.04 (m,1H), 7.03 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 3.37-3.34 (m, 1H),3.26-3.24 (m, 1H), 3.11-2.88 (m, 2H), 2.66-2.54 (m, 1H), 2.24-2.20 (m,2H), 2.01-1.83 (m, 2H).

I-202: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.00-8.99 (m, 1H), 8.56-8.54 (m, 2H),7.38-7.28 (m, 4H), 7.16-7.12 (m, 1H), 7.07-7.05 (m, 2H), 6.94-6.91 (m,2H), 3.32-3.25 (m, 2H), 3.13-3.04 (m, 1H), 2.84-2.65 (m, 1H), 2.53-2.50(m, 1H), 2.35-2.27 (m, 2H), 2.12-2.10 (m, 1H).

I-203: yellow solid. ESI-MS (M+H)⁺: 458.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 8.41-8.39 (m, 2H), 7.94-7.88 (m, 1H),7.62-7.60 (m, 1H), 7.42-7.31 (m, 5H), 7.17-7.13 (m, 1H), 7.04 (d, J=8.0Hz, 2H), 6.91 (d, J=8.0 Hz, 2H), 3.38-3.37 (m, 1H), 3.28-3.24 (m, 1H),3.06-2.90 (m, 1H), 2.66-2.53 (m, 1H), 2.26-2.22 (m, 2H), 1.99-1.85 (m,2H).

I-204: yellow solid. ESI-MS (M+H)⁺: 496.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.11 (s, 1H), 11.19 (s, 1H), 7.72-7.66(m, 1H), 7.37-7.33 (m, 5H), 7.30-7.28 (m, 1H), 7.12-7.03 (m, 2H),6.95-6.90 (m, 3H), 6.45 (d, J=8.8 Hz, 2H), 6.12 (s, 1H), 3.40-3.37 (m,1H), 3.30-3.27 (m, 1H), 3.11-2.91 (m, 1H), 2.62-2.51 (m, 1H), 2.29-2.22(m, 2H), 2.03-1.86 (m, 2H).

I-209: yellow solid. ESI-MS (M+H)⁺: 457.1.

¹H NMR: (400 MHz, CDCl₃) δ: 7.48-7.45 (m, 2H), 7.34-7.28 (m, 6H),7.25-7.23 (m, 1H), 6.90 (d, J=8.4 Hz, 2H), 4.04-4.00 (m, 2H), 3.18-3.12(m, 2H), 2.61-2.59 (m, 1H), 2.09-2.06 (m, 2H), 1.91-1.88 (m, 2H).

I-210: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, CDCl₃) δ: 9.01 (s, 1H), 8.61 (s, 2H), 7.43-7.40 (m,2H), 7.37-7.34 (m, 2H), 7.14-7.10 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.94(d, J=8.4 Hz, 2H), 4.06-4.01 (m, 2H), 3.26-3.19 (m, 2H), 2.68-2.60 (m,1H), 2.08-2.04 (m, 2H), 1.96-1.85 (m, 2H).

I-211: yellow solid. ESI-MS (M+H)⁺: 458.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.55 (s, 2H), 8.54-8.43 (m, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.35-7.31 (m, 2H), 7.21-7.18 (m,1H), 7.12-7.18 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 7.00-6.89 (d,J=8.0 Hz, 2H), 4.13 (d, J=13.2 Hz, 2H), 3.19 (t, J=7.6 Hz, 1H),2.10-2.07 (m, 2H), 1.89-1.86 (m, 2H).

I-212: yellow solid. ESI-MS (M+H)⁺: 496.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.17 (s, 1H), 7.45 (d, J=8.4 Hz, 2H),7.34-7.29 (m, 1H), 7.12-7.02 (m, 4H), 6.93 (d, J=8.8 Hz, 2H), 6.77 (d,J=7.6 Hz, 1H), 6.38 (s, 1H), 4.08-4.04 (t, J=8.0 Hz, 2H), 3.17 (t, J=7.6Hz, 1H), 2.62-2.61 (m, 1H), 2.11-2.08 (m, 2H), 1.95-1.86 (m, 2H).

I-213: yellow solid. ESI-MS (M+H)⁺: 459.1.

¹H NMR: (400 MHz, CDCl₃) δ: 7.46 (d, J=8.8 Hz, 2H), 7.34-7.28 (m, 7H),7.11-7.07 (m, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H),4.37-4.33 (m, 1H), 4.23-4.16 (m, 2H), 3.90-3.81 (m, 2H), 3.34-3.23 (m,2H).

I-214: yellow solid. ESI-MS (M+H)⁺: 461.1.

¹H NMR: (400 MHz, CDCl₃) δ: 9.05 (s, 1H), 8.64 (s, 2H), 7.42 (d, J=8.8Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.12 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.0Hz, 2H), 6.93 (d, J=8.2 Hz, 2H), 4.37-4.34 (m, 1H), 4.21-4.28 (m, 2H),3.89-3.82 (m, 2H), 3.42-3.36 (m, 2H).

I-215: yellow solid. ESI-MS (M+H)⁺: 460.1.

¹H NMR: (400 MHz, CDCl₃) δ: 8.60 (s, 2H), 8.49-8.48 (m, 1H), 7.65 (d,J=8.0 Hz, 1H), 7.42 (t, J=8.4 Hz, 2H), 7.12-7.08 (m, 1H), 7.02 (d, J=8.0Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 4.36-4.33 (m, 1H), 4.19-4.09 (m, 2H),3.88-3.81 (m, 2H), 3.43-3.35 (m, 2H).

I-216: yellow solid. ESI-MS (M+H)⁺: 498.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.23 (s, 1H), 7.39-7.31 (m, 7H),7.12-7.06 (m, 2H), 6.94 (d, J=8.0 Hz, 2H), 6.79 (d, J=8.2 Hz, 2H),4.16-4.05 (m, 1H), 3.96-3.91 (m, 2H), 3.70-3.56 (m, 2H), 3.27-3.22 (m,2H).

I-217: yellow solid. ESI-MS (M+H)⁺: 471.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.41-7.37 (m, 4H), 7.34-7.31 (m, 2H),7.27-7.24 (m, 2H), 7.16-7.15 (m, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.90 (d,J=8.2 Hz, 2H), 3.91-3.88 (m, 1H), 3.70-3.56 (m, 2H), 3.21-3.09 (m, 2H),2.09-2.07 (m, 1H), 1.69-1.65 (m, 2H), 2.09-2.07 (m, 1H), 1.49-1.40 (m,1H), 1.18-1.15 (m, 1H).

I-218: yellow solid. ESI-MS (M+H)⁺: 473.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.52 (s, 1H), 8.62 (s, 1H), 7.42-7.38 (m,4H), 7.18-7.15 (m, 1H), 7.05 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H),3.94-3.91 (m, 1H), 3.76-3.73 (m, 2H), 3.24-3.15 (m, 2H), 2.07-2.04 (m,1H), 1.70-1.61 (m, 2H), 1.49-1.46 (m, 1H), 1.17 (s, 3H).

I-219: yellow solid. ESI-MS (M+H)⁺: 472.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.60 (s, 1H), 8.44 (s, 1H), 7.65-7.63 (m,1H), 7.40-7.34 (m, 5H), 7.14-7.13 (m, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.93(d, J=7.8 Hz, 2H), 3.93-3.90 (m, 1H), 3.73-3.70 (m, 1H), 3.23-3.12 (m,2H), 2.07-2.03 (m, 1H), 1.70-1.68 (m, 2H), 1.49-1.44 (m, 1H), 1.17 (s,3H).

I-220: yellow solid. ESI-MS (M+H)⁺: 510.1.

¹H NMR: (400 MHz, DMSO-d₆) δ: 11.21 (s, 1H), 7.38-7.30 (m, 6H),7.12-7.04 (m, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.12(s, 1H), 3.94-3.91 (m, 1H), 3.73-3.70 (m, 1H), 3.34-3.27 (m, 2H),2.07-2.03 (m, 1H), 1.72-1.64 (m, 2H), 1.46-1.44 (m, 1H), 1.18 (s, 3H).

1.2 Synthesis of Compounds I-229 to I-240

General information: All evaporations were carried out in vacuo with arotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) atrt. Thin layer chromatography (TLC) was performed on silica gel plates,spots were visualized by UV light (214 and 254 nm). Purification bycolumn and flash chromatography was carried out using silica gel(200-300 mesh). Solvent systems are reported as mixtures by volume. AllNMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1Hchemical shifts are reported in δ values in ppm with the deuteratedsolvent as the internal standard. Data are reported as follows: chemicalshift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,br=broad, m=multiplet), coupling constant (Hz), integration.

LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 massspectrometer with electrospray ionization and excepted as otherwiseindicated, the general LCMS condition was as follows:

Method A (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 3.0 mL/min; mobilephase: from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0%[water+0.05% TFA] and 100% [CH₃CN+0.05% TFA] in 0.8 min, then under thiscondition for 0.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.01 min).

Method B (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0%[water+0.05% TFA] and 100% [CH₃CN+0.05% TFA] in 1.6 min, then under thiscondition for 1.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.).

Method C (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Synthetic Scheme of CompoundI-240

Synthesis of 240-01

To a solution of 2-bromo-1-phenylethanone (240-0, 1.98 g, 10.0 mmol) inEtOH (40 mL) was added sodium thiocyanate (0.82 g, 10.0 mmol), then themixture was stirred at 80° C. overnight. After completion of thereaction indicated by LCMS, the reaction mixture was concentrated underreduced pressure to give the residue, which was purified by silica gelcolumn chromatography to give 1-phenyl-2-thiocyanatoethanone (240-01,1.2 g, 68% yield) as yellow solid. MS Calcd.: 177.0; MS Found: 178.2[M+H]⁺.

Synthesis of 240-02

To a solution of 1-phenyl-2-thiocyanatoethanone (240-01, 354.0 mg, 2.0mmol) in EtOH (10 mL) was added methyl morpholine-2-carboxylate (292.5mg, 2.0 mmol), then the mixture was stirred at 60° C. overnight. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasconcentrated under reduced pressure to give the residue, which waspurified by silica gel column chromatography to give 240-02: methyl4-(4-phenylthiazol-2-yl)morpholine-2-carboxylate (400.5 mg, 66% yield)as yellow solid. MS Calcd.: 304.1; MS Found: 305.1 [M+H]⁺.

Synthesis of 240-03

To a solution of methyl 4-(4-phenylthiazol-2-yl)morpholine-2-carboxylate 240-02, (304.0 mg, 1.0 mmol) in DCM (10 mL) wasadded NB S (267.5 mg, 1.5 mmol), then the mixture was stirred at −60° C.for 0.3 hr. After completion of the reaction indicated by LCMS, thereaction mixture was quenched with saturated Na₂S₂O₃ (10 mL), dilutedwith water (10 mL) and extracted with DCM (20 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the residue,which was purified by silica gel column chromatography to give methyl4-(5-bromo-4-phenylthiazol-2-yl) morpholine-2-carboxylate 240-03, (350.5mg, 92% yield) as yellow solid. MS Calcd.: 382.0; MS Found: 383.0[M+H]⁺.

Synthesis of 240-04

To a solution of methyl 4-(5-bromo-4-phenylthiazol-2-yl)morpholine-2-carboxylate 240-03 (191.0 mg, 0.5 mmol),4′-fluorobiphenyl-4-ylboronic acid (324.2 mg, 1.5 mmol) and K₃PO₄ (318.9mg, 1.5 mmol) in dioxane (10 mL) was added 1,1′-Bis(di-t-butylphosphino)ferrocene palladium dichloride (38.2 mg, 20% w/w),then the mixture was stirred at 60° C. in microwave for 2 hours. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasconcentrated under reduced pressure to give the residue, which waspurified by silica gel column chromatography to give methyl4-(5-(4′-fluorobiphenyl-4-yl)-4-phenylthiazol-2-yl)morpholine-2-carboxylate240-04 (200.2 mg, 84% yield) as light-yellow solid. MS Calcd.: 474.1; MSFound: 475.0 [M+H]⁺.

Synthesis of I-240

To a solution of methyl4-(5-(4′-fluorobiphenyl-4-yl)-4-phenylthiazol-2-yl)morpholine-2-carboxylate (240-04, 118.5 mg, 0.25 mmol) in THF (5 mL) andH₂O (1 mL) was added LiOH.H₂O (21.5 mg, 0.50 mmol), then the mixture wasstirred at room temperature for 0.5 hour. After completion of thereaction indicated by LCMS, the reaction mixture was concentrated underreduced pressure to give the residue, which was diluted with 0.05 M HClsolution (10 ml), filtered, and the solid was collected by filtrationand washed with water to give4-(5-(4′-fluorobiphenyl-4-yl)-4-phenylthiazol-2-yl)morpholine-2-carboxylic acid (I-240, 51.2 mg, 44% yield) as off-whitesolid. MS Calcd.: 460.1; MS Found: 461.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 7.75-7.71 (m, 2H), 7.62 (d,J=8.4 Hz, 2H), 7.46 (dd, J=8.0, 2.0 Hz, 2H), 7.35-7.26 (m, 7H), 4.32(dd, J=8.8, 3.2 Hz, 1H), 4.03-4.00 (m, 1H), 3.91 (dd, J=12.4, 3.2 Hz,1H), 3.75-3.67 (m, 1H), 3.59-3.55 (m, 1H), 3.41-3.32 (m, 2H).

Synthetic Scheme of I-239

Synthesis of 239-01

To a solution of 239-0 (24 g, 121 mmol), 01-R (18.6 g, 133 mmol) andK₂CO₃ (33.6 g, 242 mmol) in dioxane (400 mL) dioxane (400 mL) mixed withwater (100 mL) was added Pd(dppf)Cl₂ (4.9 g, 6 mmol) under N₂atmosphere, the reaction mixture was heated to 80° C. and stirred for 3hr. After completion of the reaction indicated by LCMS, the reactionmixture was filtered and concentrated under reduced pressure to give theresidue, which was dissolved in water (200 mL), and extracted with EA(2×100 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give the residue, which waspurified by silica gel column chromatography to get 239-01 (20 g, 77.2%yield) as a yellow solid. MS Calcd.: 214.1; MS Found: 215.2 [M+H]⁺.

Synthesis of 239-02

To a solution of 239-01 (14 g, 65.4 mmol) in DCM (140 mL) was addedPyBr₃ (20.8 g, 65.4 mmol), the reaction mixture was stirred at r.tovernight. After completion of the reaction indicated by LCMS, thereaction mixture was concentrated under reduced pressure to give theresidue, which was purified by silica gel column chromatography to get239-02 (15 g, 78.5% yield) as a yellow solid. MS Calcd.: 292.0; MSFound: 293.0 [M+H]⁺.

Synthesis of 239-03

To a solution of 239-02 (10.4 g, 35.6 mmol) in EtOH (100 mL) was addedNaSCN (2.9 g, 35.6 mmol), the reaction mixture was stirred at r.t for 4hr. After completion of the reaction indicated by LCMS, the reactionmixture was concentrated under reduced pressure to give the residue,which was purified by silica gel column chromatography to get 239-03(7.5 g, 77.7% yield) as a yellow solid. MS Calcd.: 271.0; MS Found:272.0 [M+H]⁺.

Synthesis of 239-04

To a solution of 239-03 (4 g, 14.7 mmol) in MeOH (250 mL) was added A(2.7 g, 14.7 mmol), the reaction mixture was heated to 60° C. andstirred overnight. After completion of the reaction indicated by LCMS,the reaction mixture was filtered, the solid was washed with MeOH (5 mL)to get 239-04 (3.4 g, 58.1% yield) as a yellow solid. MS Calcd.: 398.1;MS Found: 399.0 [M+H]⁺.

Synthesis of 239-05

To a solution of 239-04 (400 mg, 1 mmol) in MeCN (20 mL) mixed withwater (5 mL) was added Na₂S₂O₄ (174 mg, 1 mmol), NaHCO₃ (84 mg, 1 mmol)and CF₃I (1.96 g, 10 mmol), the reaction mixture was stirred at r.tovernight. After completion of the reaction indicated by LCMS, thereaction mixture was diluted with DCM and washed with water, dried overNa₂SO₄, filtered and concentrated to give the residue, which waspurified by prep-HPLC to get 239-05 (190 g, 40.8% yield) as a whitesolid. MS Calcd.: 466.1; MS Found: 467.0 [M+H]⁺.

Synthesis of I-239

To a solution of 239-05 (100 mg, 0.21 mmol) in THF (5 mL) mixed withMeOH (1 mL) was added sat.LiOH (2 M, 1 mL), the reaction mixture wasstirred at r.t for 1 hr. After completion of the reaction indicated byLCMS, the reaction mixture was concentrated under reduced pressure togive the residue, the mixture was adjust pH to 6 with 2 N HCl, the solidwas collected by filtration to get the crude, which was purified byprep-HPLC to get I-239 (40 mg, 42.1% yield) as a white solid. MS Calcd.:452.1; MS Found: 453.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 13.20 (s, 1H), 7.79-7.75 (m, 4H), 7.68 (d,J=8.0 Hz, 2H), 7.32 (t, J=8.8 Hz, 2H), 4.35-4.32 (m, 1H), 4.02-3.94 ((m,2H), 3.74-3.60 (m, 2H), 3.50-3.41 (m, 2H).

Synthetic Scheme of I-238

Synthesis of 238-01

To a solution 238-0 (1.0 g, 2.53 mmol) in CH₂Cl₂ (20 mL) at −60° C. wasadded NBS (434 mg, 2.53 mmol). The mixture was stirred at −60° C. for 1h and then quenched with saturated Na₂S₂O₃ (50 mL), diluted with water(50 mL). The resulting mixture was extracted with DCM (200 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated. The crude product was purified bysilica gel column chromatograph to give 238-01 (650 mg, yield: 50.0%) asa yellow solid. MS Calcd.: 474.0; MS Found: 475.0 [M+H]⁺.

Synthesis of 238-02

To a mixture of 238-01 (240 mg, 0.5 mmol) and Pd(PPh)₃Cl₂ (70 mg, 0.1mmol) in DMF (9 mL) under N₂ was added MeZnCl (2.0 M in THF, 1.5 mL, 3.0mmol) and stirred at 100° C. for 2 h. After filtration andconcentration, the residue was purified by prep-HPLC to give 238-02 (90mg, yield: 43%) as a white solid. MS Calcd.: 410.1; MS Found: 411.0[M+H]⁺.

Synthesis of I-238

To a solution of 238-02 (90 mg, 0.22 mmol) in THF (3 mL) mixed with MeOH(1 mL) was added sat.LiOH (2 M, 1 mL), the reaction mixture was stirredat r.t for 1 hr. After completion of the reaction indicated by LCMS, thereaction mixture was concentrated under reduced pressure to give theresidue, the mixture was adjust pH to 6 with 2 N HCl, the solid wascollected by filtration to get the crude, which was purified byprep-HPLC to get I-238 (44.6 mg, 28% yield) as a white solid. MS Calcd.:396.1; MS Found: 397.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.78-7.67 (m, 4H), 7.34-7.29 (m, 2H),3.98-3.94 (m, 1H), 7.67 (d, J=13.2 Hz, 1H), 3.30-3.22 (m, 2H), 2.62-2.60(m, 1H), 2.41 (s, 3H), 2.00-1.97 (m, 1H), 1.75-1.62 (m, 3H).

Synthetic Scheme of I-237

Synthesis of 237-02

To a solution of 2-bromo-4-methylthiazole 237-01 (356.4 mg, 2.0 mmol),methyl morpholine-2-carboxylate (291.0 mg, 2.0 mmol), Cs₂CO₃ (1.3 g, 4.0mmol) and Xphos (185.6 mg, 0.4 mmol) in toluene (30 mL) was addedPd₂(dba)₃, (71.2 mg, 20% w/w), then the mixture was stirred at 113° C.overnight. After completion of the reaction indicated by LCMS, thereaction mixture was concentrated under reduced pressure to give theresidue, which was purified by silica gel column chromatography to givemethyl 4-(4-methylthiazol-2-yl)morpholine-2-carboxylate 237-02 (404.5mg, 83% yield) as light-yellow solid. MS Calcd.: 242.1; MS Found: 243.2[M+H]⁺.

Synthesis of 237-03

To a solution of methyl 4-(4-methylthiazol-2-yl)morpholine-2-carboxylate 237-02 (242.2 mg, 1.0 mmol) in DCM (10 mL) wasadded NBS (176.2 mg, 0.99 mmol), then the mixture was stirred at −60° C.for 0.2 hr. After completion of the reaction indicated by LCMS, thereaction mixture was quenched with saturated Na₂S₂O₃ (10 mL), dilutedwith water (10 mL) and extracted with DCM (20 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the residue,which was purified by silica gel column chromatography to give methyl4-(5-bromo-4-methylthiazol-2-yl)morpholine-2-carboxylate 237-03 (140.2mg, 44% yield) as light-yellow solid. MS Calcd.: 320.0; MS Found: 321.0[M+H]⁺.

Synthesis of 237-04

To a solution of methyl4-(5-bromo-4-methylthiazol-2-yl)morpholine-2-carboxylate 237-03 (140.2mg, 0.44 mmol), 4′-fluorobiphenyl-4-ylboronic acid (280.8 mg, 1.3 mmol)and K₃PO₄ (275.6 mg, 1.3 mmol) in dioxane (10 mL) was added 1,1′-Bis(di-t-butylphosphino)ferrocene palladium dichloride (28.0 mg, 20% w/w),then the mixture was stirred at 60° C. in microwave for 2 hours. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasconcentrated under reduced pressure to give the residue, which waspurified by silica gel column chromatography to give methyl4-(5-(4′-fluorobiphenyl-4-yl)-4-methylthiazol-2-yl)morpholine-2-carboxylate 237-04, (120.0 mg, 66% yield) as light-yellowsolid. MS Calcd.: 412.1; MS Found: 413.0 [M+H]⁺.

Synthesis of I-237

To a solution of methyl4-(5-(4′-fluorobiphenyl-4-yl)-4-methylthiazol-2-yl)morpholine-2-carboxylate 237-04 (120.0 mg, 0.29 mmol) in THF (5 mL) andH₂O (1 mL) was added LiOH.H₂O (24.4 mg, 0.58 mmol), then the mixture wasstirred at room temperature for 0.5 hour. After completion of thereaction indicated by LCMS, the reaction mixture was diluted with 0.05 MHCl solution (5 ml) and concentrated under reduced pressure to give theresidue, which was purified by prep-HPLC to give4-(5-(4′-fluorobiphenyl-4-yl)-4-methylthiazol-2-yl)morpholine-2-carboxylic acid I-237 (26.5 mg, 23% yield) as a whitesolid. MS Calcd.: 398.1; MS Found: 399.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (br, 1H), 7.76-7.69 (m, 4H), 7.47 (d,J=8.0 Hz, 2H), 7.33-7.28 (m, 2H), 4.33-4.29 (m, 1H), 4.01-3.97 (m, 1H),3.85 (dd, J=12.4, 3.2 Hz, 1H), 3.72-3.66 (m, 1H), 3.52 (dd, J=9.2, 3.6Hz, 1H), 3.36-3.25 (m, 2H), 2.32 (s, 3H).

Synthetic Scheme of I-236

Synthesis of 236-01

To a solution of methyl4-(5-bromo-4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)morpholine-2-carboxylate236-01 (238.0 mg, 0.5 mmol), potassium methyltrifluoroborate (183.0 mg,1.5 mmol) and K₃PO₄ (318.9 mg, 1.5 mmol) in dioxane (10 mL) was added1,1′-Bis (di-t-butylphosphino)ferrocene palladium dichloride (47.6 mg,20% w/w), then the mixture was stirred at 60° C. in microwave for 2hours. After completion of the reaction indicated by LCMS, the reactionmixture was concentrated under reduced pressure to give the residue,which was purified by silica gel column chromatography and prep-HPLC togive methyl4-(4-(4′-fluorobiphenyl-4-yl)-5-methylthiazol-2-yl)morpholine-2-carboxylate236-02 (45.8 mg, 22% yield) as light-yellow solid. MS Calcd.: 412.1; MSFound: 413.0 [M+H]⁺.

Synthesis of I-236

To a solution of methyl4-(4-(4′-fluorobiphenyl-4-yl)-5-methylthiazol-2-yl)morpholine-2-carboxylate 236-02 (45.8 mg, 0.11 mmol) in THF (5 mL) andH₂O (1 mL) was added LiOH.H₂O (10.0 mg, 0.22 mmol), then the mixture wasstirred at room temperature for 0.3 hour. After completion of thereaction indicated by LCMS, the reaction mixture was concentrated underreduced pressure to give the residue, which was diluted with 0.05 M HClsolution (5 ml), filtered, and the solid was collected by filtration andwashed with water to give4-(4-(4′-fluorobiphenyl-4-yl)-5-methylthiazol-2-yl)morpholine-2-carboxylic acid I-236 (21.75 mg, 50% yield) as off-whitesolid. MS Calcd.: 398.1; MS Found: 413.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 7.76-7.71 (m, 6H), 7.33-7.29(m, 2H), 4.29 (dd, J=8.8, 3.2 Hz, 1H), 4.00-3.97 (m, 1H), 3.82 (dd,J=12.8, 3.2 Hz, 1H), 3.72-3.66 (m, 1H), 3.51-3.47 (m, 1H), 3.29-3.21 (m,2H), 2.45 (s, 3H).

Synthetic Scheme of I-235

Synthesis of 235-01

A solution of ethyl 4-chloro-4-oxobutanoate 235-0 (10.0 g, 6.1 mmol) wasadded dropwise to 28% aqueous ammonia solution (100 mL) under icecooling, and then the mixture was allowed to warm to room temperatureand was stirred at this temperature for 0.5 h, the mixture wasconcentrated in vacuo. The residue was diluted with THF and the mixturewas filtered. The filtrate was dried over Na₂SO₄, concentrated in vacuoto give ethyl 4-amino-4-oxobutanoate 235-01 (4.9 g, 55.4% yield) aslight-yellow oil.

Synthesis of 235-02

To a solution of ethyl 4-amino-4-oxobutanoate 235-01, (4.35 g, 30.0mmol) in THF (150 mL) was added Phosphorus pentasulfide (5.73 g, 30.0mmol), then the mixture was stirred at room temperature overnight. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasfiltered and concentrated under reduced pressure to give the residue,which was purified by silica gel column chromatography to give ethyl4-amino-4-thioxobutanoate 235-02 (1.63 g, 33.7% yield) as light-yellowoil. MS Calcd.: 161.05; MS Found: 162.2 [M+H]⁺.

Synthesis of 235-04

A mixture of 2-bromo-1-(4′-fluorobiphenyl-4-yl)ethanone 235-03 (1.8 g,6.16 mmol) and ethyl 4-amino-4-thioxobutanoate 235-02 (992.5 mg, 6.16mmol) in EtOH (40 mL) was reflux for 2 h, evaporated solvent to givecrude 235-04., which was purified by silica gel column chromatography togive ethyl 3-(4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)propanoate 235-04(1.9 g, 87.2% yield) as white solid. MS Calcd.: 355.10; MS Found: 356.2[M+H]⁺.

Synthesis of 235-05

To a solution of ethyl3-(4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)propanoate 235-04 (500.0 mg,1.41 mmol) in DMSO (7.5 mL) was added CF₃I (827.9 mg, 4.22 mmol), thenthe mixture was degassed by N₂. Then dppf (150.0 mg, 0.27 mmol) wasadded followed by 30% H₂O₂ (3.4 mL). The above mixture was stirred at45° C. for 1 h, then water (20 mL) was added. The resulting mixture wasextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by silica gel column chromatograph to giveethyl3-(4-(4′-fluorobiphenyl-4-yl)-5-(trifluoromethyl)thiazol-2-yl)propanoate235-05 (260.0 mg, yield: 43.6%) as a pale yellow solid. MS Calcd.:423.09; MS Found: 424.0 [M+H]⁺.

Synthesis of I-235

To a solution of ethyl3-(4-(4′-fluorobiphenyl-4-yl)-5-(trifluoromethyl)thiazol-2-yl)propanoate235-05 (260.0 mg, 0.61 mmol) in EtOH (5 mL) and H₂O (1 mL) was addedLiOH.H₂O (103.2 mg, 2.45 mmol), then the mixture was stirred at roomtemperature for 1 hour. After completion of the reaction indicated byLCMS, the reaction mixture was concentrated under reduced pressure togive the residue, which was diluted with 1 N HCl solution (5 ml), theresulting mixture was extracted with EtOAc (5 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated. The crude product was purified by Prep-HPLCto give3-(4-(4′-fluorobiphenyl-4-yl)-5-(trifluoromethyl)-thiazol-2-yl)-propanoicacid I-235 (63.0 mg, yield: 26.0%) as white solid. MS Calcd.: 395.06; MSFound: 396.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 7.82-7.78 (m, 4H), 7.72 (d,J=8.4 Hz, 2H), 7.33 (t, J=8.8 Hz, 2H), 3.32 (t, J=7.0 Hz, 2H), 2.82 (t,J=7.0 Hz, 2H).

Synthetic Scheme of I-234

Synthesis of 234-01

To a solution of ethyl3-(4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)propanoate 234-0 (1.0 g, 2.8mmol) in DCM (50 mL) was added NBS (602.0 mg, 3.4 mmol). The mixture wasstirred at room temperature overnight and then quenched with saturatedNa₂S₂O₃ (5 mL), diluted with water (10 mL). The resulting mixture wasextracted with DCM (20 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by silica gel column chromatograph to giveethyl 3-(5-bromo-4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)propanoate234-01 (816.0 mg, yield: 66.9%) as a pale yellow solid. MS Calcd.:433.01; MS Found: 433.8 [M+H]⁺.

Synthesis of 234-02

To a mixture of ethyl3-(5-bromo-4-(4′-fluorobiphenyl-4-yl)thiazol-2-yl)propanoate 234-01(400.0 mg, 0.92 mmol) and Phenylboronic acid (338.0 mg, 2.77 mmol) in1,4-dioxane (6 mL) were added 1,1′-Bis (di-t-butylphosphino)ferrocenepalladium dichloride (60.0 mg, 0.09 mmol), K₃PO₄ (587.0 mg, 2.77 mmol)and water (1 mL). The mixture was stirred at microwave 60° C. for 2 h.After filtration and concentration, the residue was purified by silicagel column chromatograph to give ethyl3-(4-(4′-fluorobiphenyl-4-yl)-5-phenylthiazol-2-yl)propanoate 234-02(350.0 mg, yield: 87.9%) as a pale yellow solid. MS Calcd.: 431.14; MSFound: 432.1 [M+H]⁺.

Synthesis of I-234

To a solution of ethyl3-(4-(4′-fluorobiphenyl-4-yl)-5-phenylthiazol-2-yl)propanoate 234-02(200.0 mg, 0.46 mmol) in EtOH (4 mL) and H₂O (1 mL) was added LiOH.H₂O(77.8 mg, 1.86 mmol), then the mixture was stirred at room temperaturefor 1 hour. After completion of the reaction indicated by LCMS, thereaction mixture was concentrated under reduced pressure to give theresidue, which was diluted with 1 N HCl solution (5 ml), the resultingmixture was extracted with EtOAc (5 mL×3). The combined organic layerswere washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by Prep-HPLC to give3-(4-(4′-fluorobiphenyl-4-yl)-5-phenylthiazol-2-yl)propanoic acid I-234(47.1 mg, yield: 25.1%) as off-white solid. MS Calcd.: 403.10; MS Found:404.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 7.74-7.71 (m, 2H), 7.62-7.60(m, 2H), 7.53-7.51 (m, 2H), 7.42-7.36 (m, 5H), 7.28 (t, J=9.0 Hz, 2H),3.26 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H).

Synthetic Scheme of I-233

Synthesis of 233-01

To a solution of 233-0 (3.1 g, 11.4 mmol) in EtOH (250 mL) was added A(1.6 g, 14.7 mmol), the reaction mixture was heated to 85° C. overnight.After completion of the reaction indicated by LCMS, the solvent wasremoved in vacuo and purified by CC to obtain 233-01 (2.4 g, 53% yield)as a yellow solid. MS Calcd.: 396.1; MS Found: 397.1 [M+H]⁺.

Synthesis of 233-02

To a solution of 233-01 (340 mg, 0.86 mmol) in MeCN (20 mL) mixed withwater (5 mL) was added Na₂S₂O₄ (149 mg, 0.86 mmol), NaHCO₃ (72 mg, 0.86mmol) and CF₃I (1.7 g, 8.6 mmol), the reaction mixture was stirred atr.t overnight. After completion of the reaction indicated by LCMS, thereaction mixture was diluted with DCM and washed with water, dried overNa₂SO₄, filtered and concentrated to give the residue, which waspurified by prep-HPLC to get 233-02 (300 mg, 75% yield) as a whitesolid. MS Calcd.: 464.1; MS Found: 465.0 [M+H]⁺.

Synthesis of I-233

To a solution of 233-02 (120 mg, 0.26 mmol) in THF (5 mL) mixed withMeOH (1 mL) was added sat.LiOH (2 M, 1 mL), the reaction mixture wasstirred at r.t for 1 hr. After completion of the reaction indicated byLCMS, the reaction mixture was concentrated under reduced pressure togive the residue, the mixture was adjust pH to 6 with 2 N HCl, the solidwas collected by filtration to get the crude, which was purified byprep-HPLC to get I-233 (33 mg, 28% yield) as a white solid. MS Calcd.:450.1; MS Found: 451.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 7.94-7.74 (m, 4H), 7.67 (d,J=8.4 Hz, 2H), 7.32 (m, 2H), 4.03-3.99 (m, 1H), 3.71-3.67 (m, 1H),3.40-3.34 ((m, 2H), 2.65-2.59 (m, 1H), 2.01-1.96 (m, 1H), 1.77-1.63 (m,3H).

Synthetic Scheme of I-232

Synthesis of 232-01

To a mixture of 232-0 (240 mg, 0.5 mmol), cyclopropylboronic acid (129mg, 1.5 mmol), K₃PO₄ (211 mg, 1.5 mmol) and Pd118 (65 mg, 0.1 mmol) inDMF (9 mL) under N₂ was heated to 80° C. in microwave for 1 h. Afterfiltration and concentration, the residue was purified by CC to give232-01 (110 mg, yield: 50%) as a white solid. MS Calcd.: 436.2; MSFound: 437.0 [M+H]⁺.

Synthesis of I-232

To a solution of 232-01 (110 mg, 0.25 mmol) in THF (3 mL) mixed withMeOH (1 mL) was added LiOH (2 M, 1 mL), the reaction mixture was stirredat r.t for 1 hr. After completion of the reaction indicated by LCMS, thereaction mixture was concentrated under reduced pressure to give theresidue, the mixture was adjusted pH to 6 with 2 N HCl, the solid wascollected by filtration to get the crude, which was purified byprep-HPLC to get I-232 (40.1 mg, 38% yield) as a white solid. MS Calcd.:422.1; MS Found: 423.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.49 (s, 1H), 7.91 (d, J=8.4 Hz, 2H),7.77-7.69 (m, 4H), 7.33-3.28 (m, 2H), 3.96-3.91 (m, 1H), 3.65-3.61 (m,1H), 3.21-3.10 (m, 2H), 2.55-2.50 (m, 1H), 2.15-2.10 (m, 1H), 1.99-1.95(m, 1H), 1.60-1.57 (m, 3H), 1.07-1.01 (m, 2H), 0.57-0.50 (m, 2H).

Synthetic Scheme of I-231

Synthesis of 231-02

To a solution of 231-01 (1.00 g, 3.69 mmol) in EtOH (10 mL) was addedmethyl morpholine-3-carboxylate (0.54 g, 3.72 mmol), then the mixturewas stirred at reflux overnight. After completion of the reactionindicated by LCMS, the reaction mixture was concentrated under reducedpressure to give the residue, which was purified by silica gel columnchromatography to give 231-02 (0.74 g, 50% yield) as a yellow solid. MSCalcd.: 398.1; MS Found: 399.2 [M+H]⁺.

Synthesis of 231-03

To a solution of 231-02 (430 mg, 1.08 mmol) in DCM (5 mL) was added NBS(150 mg, 2.64 mmol), then the mixture was stirred at r.t. for 5 h. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasquenched with saturated Na₂S₂O₃ (5 mL), diluted with water (5 mL) andextracted with DCM (20 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the residue, which was purified by silica gelcolumn chromatography to give 231-03 (372 mg, 72% yield) as a yellowsolid. MS Calcd.: 476.0; MS Found: 477.0 [M+H]⁺.

Synthesis of 231-04

To a solution of 231-03 (410 mg, 0.86 mmol), phenylboronic acid (315 mg,2.58 mmol) and K₃PO₄ (547 mg, 2.58 mmol) in dioxane (6 mL) was added1,1′-Bis (di-t-butylphosphino)ferrocene palladium dichloride (70 mg,0.09 mmol), then the mixture was stirred at 50° C. over night. Aftercompletion of the reaction indicated by LCMS, the reaction mixture wasconcentrated under reduced pressure to give the residue, which waspurified by silica gel column chromatography to give 231-04 (316 mg, 77%yield) as a light-yellow solid. MS Calcd.: 474.1; MS Found: 475.1[M+H]⁺.

Synthesis of I-231

To a solution of 231-04 (156 mg, 0.33 mmol) in THF/MeOH/H₂O (4 mL/1 mL/1mL) was added LiOH.H₂O (24 mg, 1.00 mmol), then the mixture was stirredat room temperature for 3 hour. After completion of the reactionindicated by LCMS, the reaction mixture was concentrated under reducedpressure to give a residue which was acidify by 1N HCl to PH=6 andfiltrated. The precipitate was purified by prep-HPLC (basic method) togive I-231 (49 mg, 32% yield) as a white solid. MS Calcd.: 460.1; MSFound: 461.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 7.72-7.68 (m, 2H), 7.57-7.51 (m, 2H),7.50-7.47 (m, 2H), 7.37-7.32 (m, 2H), 7.30-7.24 (m, 5H), 4.37 (d, J=10.8Hz, 1H), 4.23-4.17 (m, 1H), 3.91-3.85 (m, 1H), 3.68-3.61 (m, 2H),3.47-3.41 (m, 2H).

Synthetic Scheme of I-230

Synthesis of 230-1

To a solution of 1-(4′-fluorobiphenyl-4-yl) propan-1-one (1.0 g, 4.38mmol) in DCM (20 mL) was added Br₂ (0.77 g, 4.82 mmol) at 0° C. Then thereaction was warmed to room temperature and stirred for 3 hours. Thereaction was quenched with NaHCO₃ solution (30 mL). The organic layerwas separated and washed with brine (30 mL), dried over sodium sulfate,filtered and concentrated. Desired product was obtained as yellow solid(580 mg, Yield: 43.1%).

Synthesis of 230-2

To a solution of 2-bromo-1-(4′-fluorobiphenyl-4-yl) propan-1-one (580mg, 1.89 mmol) in EtOH (20 mL) was added NaSCN (306 mg, 3.78 mmol). Thereaction was heated to 90° C. and stirred at 90° C. for 3 hours. Thesolvent was concentrated. The solid was dissolved in EtOAc (50 mL). Themixture was washed with waster (40 mL). The organic layer was washedwith brine (30 mL), dried over sodium sulfate, filtered andconcentrated. Desired product was obtained as yellow solid (570 mg,Crude Yield: ˜100%).

Synthesis of 230-3

To a solution of 1-(4′-fluorobiphenyl-4-yl)-2-thiocyanatopropan-1-one(570 mg, 1.99 mmol) in EtOH (10 mL) was added ethyl3-amino-2-methylpropanoate (524 mg, 3.99 mmol). The reaction was heatedto 90° C. and stirred at 90° C. overnight. The solvent was concentrated.The crude product was purified by column chromatography. Desired productwas obtained as yellow solid (77 mg, Yield: 9.7%).

Synthesis of I-230

To ethyl3-(4-(4′-fluorobiphenyl-4-yl)-5-methylthiazol-2-ylamino)-2-methylpropanoate(77 mg, 0.19 mmol) was added MeOH (4 mL), THF (1 mL) and water (1 mL).The LiOH (9 mg, 0.38 mmol) was added into the reaction. The mixture wasstirred at room temperature for 5 hours. The reaction was quenched by 1N HCl solution (20 mL) and the mixture was stirred for 1 hour. Themixture was filtered. The wet cake was dried. Desired product wasobtained as white solid (70 mg, Yield: 97.8%). MS Calcd.: 370.1; MSFound: 371.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.28 (3H, d, J=7.2 Hz), 2.34 (3H, s), 2.94(1H, dd, 7.6 Hz), 3.33-3.36 (1H, m), 3.55-3.62 (1H, m), 7.06 (2H, t,J=8.8, 8.8 Hz), 7.46-7.58 (6H, m), 9.43 (1H, s), 13.56 (1H, s)

Synthetic Scheme of I-229

Synthesis of 229-1

1-(4-bromophenyl) ethanone (5.0 g, 25.12 mmol), 4-fluorophenylboronicacid (4.6 g, 32.66 mmol), K₂CO₃ (6.9 g, 50.24 mmol) Pd(PPh₃)₄ (0.5 g),dioxane (20 mL) and water (2 mL) was charged into a reactor protectedwith N₂. The reaction was heated to 90° C. and stirred for 2 hours. Themixture was filtered via diatomite and washed cake with EtOAc (50 mL).The mixture was washed with water (20 mL). The organic layer wasconcentrated. The crude product was purified by column chromatography.Desired product was obtained as white solid (5.3 g, Yield: 98.5%).

Synthesis of 229-2

To a solution of 1-(4′-fluorobiphenyl-4-yl) ethanone (500 mg, 2.33 mmol)in EtOAc (20 mL) was added CuBr₂ (1.04 g, 4.67 mmol). The reaction washeated to reflux and stirred overnight. The mixture was cooled to roomtemperature. The mixture was filtered and washed cake with EtOAc (20mL). The filtrate was washed with NH₄Cl solution (30 mL*₃) and brine (30mL), dried over sodium sulfate, filtered and concentrated. Desiredproduct was obtained as yellow solid (680 mg, Yield: 99.4%).

Synthesis of 229-3

To a solution of 2-bromo-1-(4′-fluorobiphenyl-4-yl) ethanone (680 mg,2.32 mmol) in EtOH (20 mL) was added NaSCN (376 mg, 4.64 mmol). Thereaction was heated to 90° C. and stirred at 90° C. for 3 hours. Thesolvent was concentrated. The solid was dissolved in EtOAc (50 mL). Themixture was washed with waster (40 mL). The organic layer was washedwith brine (30 mL), dried over sodium sulfate, filtered andconcentrated. Desired product was obtained as yellow solid (600 mg,Yield: 95.3%).

Synthesis of 229-4

To a solution of 1-(4′-fluorobiphenyl-4-yl)-2-thiocyanatoethanone (500mg, 1.84 mmol) in i-PrOH (20 mL) was added 3-amino-2-methylpropanoicacid (285 mg, 2.76 mmol) and AcOH (223 mg, 3.68 mmol). The reaction washeated to 90° C. and stirred at 90° C. overnight. The solvent wasconcentrated. Desired crude product was obtained as yellow oil (1.4 g,Yield: 200%).

Synthesis of 229-5

To a solution of 3-(4-(4′-fluorobiphenyl-4-yl)thiazol-2-ylamino)-2-methylpropanoic acid (1.3 g, 3.65 mmol) in MeOH (30mL) was added SOCl₂ (0.87 g, 7.29 mmol) at 0° C. The mixture was stirredat 0° C. for 3 hours. The solvent was concentrated. The crude productwas purified by column chromatography. Desired product was obtained asyellow solid (540 mg, Yield: 39.9%).

Synthesis of 229-6

Methyl 3-(4-(4′-fluorobiphenyl-4-yl)thiazol-2-ylamino)-2-methylpropanoate (540 mg, 1.46 mmol), Na₂S₂O₄ (507mg, 2.91 mmol), NaHCO₃ (245 mg, 2.91 mmol), MeCN (10 mL) and water (5mL) was charged into a pressure tank reactor. CF₃I (about 5 g) wascharged into the mixture. The reaction was stirred at room temperatureovernight. The reaction was extracted with EtOAc (30 mL). The mixturewas washed with waster (40 mL). The organic layer was washed with brine(30 mL), dried over sodium sulfate, filtered and concentrated. Desiredproduct was obtained as yellow solid (400 mg, Yield: 62.6%).

Synthesis of I-229

To methyl 3-(4-(4′-fluorobiphenyl-4-yl)-5-(trifluoromethyl)thiazol-2-ylamino)-2-methylpropanoate (200 mg, 0.46 mmol) was added THF(2 mL) and water (2 mL). The LiOH (13 mg, 0.55 mmol) was added into thereaction. The mixture was stirred at room temperature until materialdisappeared in TLC (0.5˜1 hour). The reaction was quenched by 1 N HClsolution (20 mL) and the mixture was extracted with EtOAc (20 mL). Thesolvent was concentrated. The crude product was purified by pre-HPLC.Desired product was obtained as orange red solid (25 mg, Yield: 12.9%).MS Calcd.: 424.1; MS Found: 424.9 [M+H]+.

1H NMR (400 MHz, CDCl₃) δ: 1.06 (3H, d, J=6.8 Hz), 2.72-2.78 (1H, m),3.33-3.40 (2H, m), 7.32 (2H, t, J=8.8, 8.8 Hz), 7.59 (2H, d, J=8.0 Hz),7.74-7.80 (4H, m), 8.48-8.51 (1H, m)

Example 2. Compound Testing in Human eIF4E/4G2 Binding Assay

Human eIF4E (aa 28-217) with a C-terminal His-tag was expressed in E.coli in inclusion bodies. The protein was solubilized with 8 M urea andpurified under denaturing conditions using nickel-charged HisTrap HPcolumns (GE Healthcare). The purified protein was then refolded bydiluting in 20 mM Hepes pH 7.0, 0.5 M NaCl, 1 mM DTT, 1 mM EDTA, 0.5 Marginine plus 6 M urea, and then dialyzing overnight into the samebuffer without the urea. The protein was further dialyzed into 20 mMHepes, pH 6.5, 50 mM NaCl, 1 mM EDTA, 1 mM DTT, and concentrated usingHitrap SP sepharose FF columns (GE Healthcare). The concentrated proteinwas dialyzed into 20 mM Hepes, pH 7.0, 0.5M NaCl, 5 mM DTT and 10%glycerol, and stored at −80° C. until use.

Test compounds (3.43 mM stock in DMSO) were diluted 2-fold in series inDMSO (10 concentration points). Compound solutions (1.2 μl/well) wereadded into black 384-well polypropylene microplates (Matrix, ThermalScientific). Twenty-two microliters per well of Assay Buffer (50 mMNaPi, pH 6.5, 50 mM KCl, 1 mM DTT and 0.5 mg/ml gamma globulin) andeight microliters per well of 82.5 nM purified eIF4E in Assay Bufferwere added. The samples were incubated at room temperature (20-23° C.)for 15 min. Biotin labeled 4G2 peptide(Ac-Lys-Gln-Tyr-Asp-Arg-Glu-Phe-Leu-Leu-Asp-Phe-Gln-Phe-Met-Pro-Lys(Aha-Bio)-NH2,1.75 μM stock in DMSO) was diluted to 0.14 μM in Assay Buffer (withoutDTT) and 5 μl/well was added. The samples were incubated at roomtemperature for 15 min. Five microliters per well of 6.4 nMEu-streptavidin (Eu-SA, Perkin Elmer) and 80 nM Allophycocyanin(APC)-anti His antibody (Columbia Biosciences) in Assay Buffer (withoutDTT) were then added and the samples were incubated at room temperaturefor 20 min.

Assay signals were monitored by reading excitation at 340 nm andemission fluorescence at 615 nm and 665 nm on an Envision reader (PerkinElmer). Normalized TR-FRET (time-resolved fluorescence resonance energytransfer) assay signal (Rn) was calculated by the formula:

Rn=[(A−Ba−C×D)/(D−Bd)]×(Dc−Bd)

Where A is the fluorescence intensity of the sample at 665 nm,D is the fluorescence intensity of the sample at 615 nm,Ba and Bd are plate backgrounds at 665 nm and 615 nm, respectively,Dc is the fluorescence intensity of 0.78 nM Eu-SA in the assay buffer at615 nmThe cross-talk factor (C) is determined by the following formula:

C=(Ac−Ba)/(Dc−Bd)

Where Ac is the fluorescence intensity of 0.78 nM Eu-SA in the assaybuffer at 665 nm.

IC50 values were calculated using xLFit program (IDBS). Table 2 belowlists IC50 of some compounds, wherein A represents IC50 <5 uM; Brepresents IC50 between 5-25 uM; and C represents IC50 >25 uM.

TABLE 2 IC50 of Certain Exemplary Compounds. Comp. No. IC50 I-1 C I-2 CI-3 C I-4 C I-5 C I-6 C I-7 C I-8 C I-9 C I-10 C I-11 C I-12 C I-13 CI-14 C I-15 C I-16 C I-17 C I-18 B I-19 C I-20 C I-21 C I-22 C I-23 CI-24 C I-25 C I-26 C I-27 C I-28 C I-29 C I-30 C I-31 C I-32 C I-33 CI-34 C I-35 C I-36 C I-37 C I-38 C I-39 C I-40 C I-41 C I-42 C I-43 CI-44 C I-45 C I-46 C I-47 C I-52 C I-53 C I-54 C I-55 C I-56 C I-57 CI-58 C I-59 C I-60 C I-61 C I-62 C I-63 C I-64 B I-65 B I-66 A I-67 CI-68 C I-69 B I-70 C I-71 B I-72 A I-73 C I-74 B I-75 B I-76 C I-77 BI-78 C I-79 C I-80 B I-81 C I-82 B I-83 A I-84 C I-85 C I-86 B I-87 CI-88 B I-89 A I-90 C I-91 C I-92 B I-93 C I-94 B I-95 B I-96 C I-97 CI-98 B I-99 C I-100 B I-101 B I-102 C I-103 C I-104 B I-105 B I-106 AI-107 C I-108 B I-109 A I-110 C I-111 A I-112 C I-113 C I-114 A I-115 CI-116 A I-117 C I-118 C I-119 B I-120 C I-121 B I-122 A I-123 C I-124 CI-125 A I-126 C I-127 B I-128 A I-129 C I-130 C I-131 B I-136 A I-137 CI-138 B I-139 B I-140 A I-141 C I-142 C I-143 A I-144 A I-145 C I-146 BI-147 A I-148 C I-149 B I-150 C I-151 C I-152 B I-153 C I-154 A I-155 CI-156 C I-157 B I-158 A I-159 C I-160 C I-161 B I-162 C I-163 B I-164 CI-165 C I-166 B I-167 C I-168 A I-169 C I-170 C I-171 B I-172 B I-173 CI-174 C I-175 C I-176 C I-177 B I-178 C I-179 C I-180 C I-181 C I-182 AI-183 C I-184 C I-185 A I-186 A I-187 C I-188 C I-189 B I-190 C I-191 AI-192 C I-193 C I-194 B I-195 C I-196 A I-197 C I-198 C I-199 B I-200 CI-201 A I-202 C I-203 C I-204 B I-209 A I-210 C I-211 C I-212 B I-213 AI-214 C I-215 C I-216 C I-217 A I-218 C I-219 B I-220 A I-221 A I-222 AI-223 A I-224 A I-225 A I-226 A I-227 A I-228 A I-229 A I-230 B I-231 AI-232 A I-233 A I-234 A I-235 B I-236 B I-237 B I-238 B I-239 B I-240 A

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: L¹ is a bond, O,or S; R¹ is an optionally substituted ring selected from phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; L² is a C₁₋₈ bivalent straight or branchedhydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbonchain are optionally and independently replaced with —N(R)— or -Cy-;each R is independently selected from hydrogen or optionally substituted—C₁₋₆ aliphatic; each -Cy- is independently an optionally substitutedbivalent ring selected from a 3-6 membered monocyclic, saturated orpartially unsaturated, carbocyclic ring, or a 3-6 membered monocyclic,saturated or partially unsaturated, heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; R²is —COOR; and R³ is R, halogen, or an optionally substituted ringselected from phenyl, an 8-10 membered bicyclic aromatic carbocyclicring, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, oran 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L^(r) is a bond.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L^(r) is O. 4-5.(canceled)
 6. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is phenyl substituted with 1-4 substituentsindependently selected from —CN, halogen, —OH, unsubstituted —O—C₁₋₆alkyl, and an unsubstituted 3-8 membered monocyclic saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.
 7. Thecompound of claim 6, or a pharmaceutically acceptable salt thereof,wherein R¹ is


8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is an unsubstituted 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.
 9. (canceled)
 10. The compound of claim 8,or a pharmaceutically acceptable salt thereof, wherein R¹ is


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L² is a C₁₋₈ bivalent straight or branched hydrocarbonchain, wherein 1 methylene unit of the hydrocarbon chain is optionallyreplaced with —N(R)— or -Cy-.
 12. (canceled)
 13. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each -Cy- isindependently a bivalent C₃₋₆ monocyclic saturated carbocyclic ringoptionally substituted 1-4 times with unsubstituted —C₁₋₆alkyl.
 14. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each -Cy- is independently a bivalent 3-6 membered monocyclicsaturated heterocyclic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, optionally substituted 1-4times with unsubstituted —C₁₋₆alkyl.
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L² is

16-18. (canceled)
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is —COOH. 20-21. (canceled)
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is optionally substituted phenyl.
 23. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R³ is anoptionally substituted 5-6-membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.
 24. The compound of claim 23, or a pharmaceutically acceptablesalt thereof, wherein R³ is


25. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R³ is an optionally substituted 8-10 membered bicyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.
 26. The compound of claim 25, or apharmaceutically acceptable salt thereof, wherein R³ is


27. (canceled)
 28. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, selected from Table
 1. 29. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.
 30. A method for treating cancer in a patientcomprising administering to the patient the compound of claim 1, or apharmaceutically acceptable salt thereof.